Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-30 (of 67 Records) |
Query Trace: Gage K[original query] |
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Yersinia pestis Δail Mutants Are Not Susceptible to Human Complement Bactericidal Activity in the Flea.
Kolodziejek AM , Bearden SW , Maes S , Montenieri JM , Gage KL , Hovde CJ , Minnich SA . Appl Environ Microbiol 2023 89 (2) e0124422 Ail confers serum resistance in humans and is a critical virulence factor of Y. pestis, the causative agent of plague. Here, the contribution of Ail for Y. pestis survival in the flea vector was examined. Rat or human but not mouse sera were bactericidal against a Y. pestis Δail mutant at 28°C in vitro. Complement components deposited rapidly on the Y. pestis surface as measured by immunofluorescent microscopy. Ail reduced the amount of active C3b on the Y. pestis surface. Human sera retained bactericidal activity against a Y. pestis Δail mutant in the presence of mouse sera. However, in the flea vector, the serum protective properties of Ail were not required. Flea colonization studies using murine sera and Y. pestis KIM6(+) wild type, a Δail mutant, and the Δail/ail(+) control showed no differences in bacterial prevalence or numbers during the early stage of flea colonization. Similarly, flea studies with human blood showed Ail was not required for serum resistance. Finally, a variant of Ail (Ail(F100V E108_S109insS)) from a human serum-sensitive Y. pestis subsp. microtus bv. Caucasica 1146 conferred resistance to human complement when expressed in the Y. pestis KIM6(+) Δail mutant. This indicated that Ail activity was somehow blocked, most likely by lipooligosaccharide, in this serum sensitive strain. IMPORTANCE This work contributes to our understanding of how highly virulent Y. pestis evolved from its innocuous enteric predecessor. Among identified virulence factors is the attachment invasion locus protein, Ail, that is required to protect Y. pestis from serum complement in all mammals tested except mice. Murine sera is not bactericidal. In this study, we asked, is bactericidal sera from humans active in Y. pestis colonized fleas? We found it was not. The importance of this observation is that it identifies a protective niche for the growth of serum sensitive and nonsensitive Y. pestis strains. |
Cervical Precancers and Cancers Attributed to HPV Types by Race and Ethnicity: Implications for Vaccination, Screening, and Management.
Mix J , Saraiya M , Hallowell BD , Befano B , Cheung LC , Unger ER , Gargano JW , Markowitz LE , Castle PE , Raine-Bennett T , Walker J , Zuna R , Schiffman M , Wentzensen N , Gage JC . J Natl Cancer Inst 2022 114 (6) 845-853 BACKGROUND: Racial and ethnic variations in attribution of cervical precancer and cancer to HPV types may result in different HPV vaccine protection, screening test coverage, and clinical management. METHODS: Pooling data from seven U.S. studies, we calculated the proportional attribution of precancers and cancers to HPV types using HPV DNA typing from diagnosis. All statistical tests were 2-sided. RESULTS: For all racial and ethnic groups, most cervical intraepithelial neoplasia grade 3 (CIN3) (n=5,526) and squamous cell carcinoma (SCC) cases (n=1,138) were attributed to types targeted by the 9-valent vaccine. A higher proportion of CIN3s were attributed to non-vaccine HPV types among non-Hispanic Black women (15.8%) compared with non-Hispanic Asian or Pacific Islander (9.7%, P=.002), non-Hispanic White (9.2%, P<.001), and Hispanic women (11.3%, P=.004). The proportion of SCCs attributed to 9-valent types was similar by race and ethnicity (90.4%-93.8%, P=.80). A higher proportion of CIN3s were attributed to non-vaccine HPV35 among non-Hispanic Black (9.0%) compared with non-Hispanic Asian or Pacific Islander (2.2%), non-Hispanic White (2.5%), and Hispanic women (3.0%, all P<.001). Compared with CIN3, the proportion of SCCs attributed to HPV35 among Non-Hispanic Black women (3.2%) was lower and closer to other groups (0.3%-2.1%, P=.70). CONCLUSION: The 9-valent HPV vaccine will prevent nearly all cervical precancers and invasive cancers among major racial and ethnic groups in the United States. Adding HPV35 to vaccines could prevent a small percentage of CIN3s and SCCs, with greater potential impact for CIN3s among Black women. HPV screening tests target high-risk HPV types, including HPV35. Future genotyping triage strategies could consider the importance of HPV35 and other HPV16 related types. |
Epidemiology, Ecology and Prevention of Plague in the West Nile Region of Uganda: The Value of Long-Term Field Studies
Eisen RJ , Atiku LA , Enscore RE , Mpanga JT , Acayo S , Mead PS , Apangu T , Yockey BM , Borchert JN , Beard CB , Gage KL . Am J Trop Med Hyg 2021 105 (1) 18-23 Plague, a fleaborne rodent-associated zoonosis, is a neglected disease with most recent cases reported from east and central Africa and Madagascar. Because of its low incidence and sporadic occurrence, most of our knowledge of plague ecology, prevention, and control derives from investigations conducted in response to human cases. Long-term studies (which are uncommon) are required to generate data to support plague surveillance, prevention, and control recommendations. Here we describe a 15-year, multidisciplinary commitment to plague in the West Nile region of Uganda that led to significant advances in our understanding of where and when persons are at risk for plague infection and how to reduce morbidity and mortality. These findings provide data-driven support for several existing recommendations on plague surveillance and prevention and may be generalizable to other plague foci. |
The changing triad of plague in Uganda: invasive black rats (Rattus rattus), indigenous small mammals, and their fleas
Enscore RE , Babi N , Amatre G , Atiku L , Eisen RJ , Pepin KM , Vera-Tudela R , Sexton C , Gage KL . J Vector Ecol 2020 45 (2) 333-355 Rattus rattus was first reported from the West Nile Region of Uganda in 1961, an event that preceded the appearance of the first documented human plague outbreak in 1970. We investigated how invasive R. rattus and native small mammal populations, as well as their fleas, have changed in recent decades. Over an 18-month period, a total of 2,959 small mammals were captured, sampled, and examined for fleas, resulting in the identification of 20 small mammal taxa that were hosts to 5,109 fleas (nine species). Over three-fourths (75.8%) of captured mammals belonged to four taxa: R. rattus, which predominated inside huts, and Arvicanthis niloticus, Mastomys sp., and Crocidura sp., which were more common outside huts. These mammals were hosts for 85.8% of fleas collected, including the efficient plague vectors Xenopsylla cheopis and X. brasiliensis, as well as likely enzootic vectors, Dinopsyllus lypusus and Ctenophthalmus bacopus. Flea loads on small mammals were higher in certain environments in villages with a recent history of plague compared to those that lacked such a history. The significance of these results is discussed in relation to historical data, the initial spread of plague in the WNR and the continuing threat posed by the disease. |
Ecology and management of plague in diverse communities of rodents and fleas
Eads DA , Biggins DE , Gage KL . Vector Borne Zoonotic Dis 2020 20 (12) 888-896 Plague originated in Asia as a flea-borne zoonosis of mammalian hosts. Today, the disease is distributed nearly worldwide. In western United States of America, plague is maintained, transmitted, and amplified in diverse communities of rodents and fleas. We examined flea diversity on three species of prairie dogs (Cynomys spp., PDs) and six species of sympatric small rodents in Montana and Utah, United States of America. Among 2896 fleas, 19 species were identified; 13 were found on PDs and 9 were found on small rodents. In Montana, three flea species were found on PDs; the three species parasitize PDs and mice. In Utah, 12 flea species were found on PDs; the 12 species parasitize PDs, mice, voles, chipmunks, ground squirrels, rock squirrels, and marmots. Diverse flea communities and their willingness to parasitize many types of hosts, across multiple seasons and habitats, may favor plague maintenance and transmission. Flea parasitism on Peromyscus deer mice varied directly with elevation. Fleas are prone to desiccation, and might prosper at higher, mesic elevations; in addition, Peromyscus nest characteristics may vary with elevation. Effective management of plague is critical. Plague management is probably most effective when encompassing communities of rodents and fleas. Treatment of PD burrows with 0.05% deltamethrin dust, which suppressed fleas on PDs for >365 days, suppressed fleas on small rodents for at least 58 days. At one site, deltamethrin suppressed fleas on small rodents for at least 383 days. By simultaneously suppressing fleas on PDs and small rodents, deltamethrin should promote ecosystem resilience and One Health objectives. |
Assessment of ICD-10-CM code assignment validity for case finding of outpatient anticoagulant-related bleeding among Medicare beneficiaries
Shehab N , Ziemba R , Campbell KN , Geller AI , Moro RN , Gage BF , Budnitz DS , Yang TH . Pharmacoepidemiol Drug Saf 2019 28 (7) 951-964 PURPOSE: To assess performance of International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code assignments for identifying bleeding events resulting in emergency department visits and hospitalizations among outpatient Medicare beneficiaries prescribed anticoagulants. METHODS: Performance of 206 ICD-10-CM code assignments indicative of bleeding, five anticoagulant adverse effect/poisoning codes, and five coagulopathy codes (according to Medicare Parts A and B claims) as assessed among Medicare fee-for-service beneficiaries prescribed anticoagulants between October 1, 2015 and September 30, 2016 (according to Part D claims). Structured medical record review was the gold standard for validating the presence of anticoagulant-related bleeding. Sensitivity was adjusted to correct for partial verification bias due to sampling design. RESULTS: Based on the study sample of 1166 records (583 cases, 583 controls), 57 of 206 codes yielded the optimal performance for anticoagulant-related bleeding (diagnostic odds ratio, 51; positive predictive value (PPV), 75.7% [95% CI, 72.0%-79.1%]; adjusted sensitivity, 70.0% [95% CI, 63.2%-77.7%]). Codes for intracranial bleeding demonstrated the highest PPV (85.0%) and adjusted sensitivity (91.0%). Bleeding codes in the primary position demonstrated high PPV (86.9%), but low adjusted sensitivity (36.0%). The adjusted sensitivity improved to 69.5% when codes in a secondary position were added. Only one adverse effect/poisoning code was used, appearing in 7.8% of cases and controls (PPV, 71.4% and adjusted sensitivity, 6.8%). CONCLUSIONS: Performance of ICD-10-CM code assignments for bleeding among patients prescribed anticoagulants varied by bleed type and code position. Adverse effect/poisoning codes were not commonly used and would have missed over 90% of anticoagulant-related bleeding cases. |
Historical and genomic data reveal the influencing factors on global transmission velocity of plague during the Third Pandemic.
Xu L , Stige LC , Leirs H , Neerinckx S , Gage KL , Yang R , Liu Q , Bramanti B , Dean KR , Tang H , Sun Z , Stenseth NC , Zhang Z . Proc Natl Acad Sci U S A 2019 116 (24) 11833-11838 Quantitative knowledge about which natural and anthropogenic factors influence the global spread of plague remains sparse. We estimated the worldwide spreading velocity of plague during the Third Pandemic, using more than 200 years of extensive human plague case records and genomic data, and analyzed the association of spatiotemporal environmental factors with spreading velocity. Here, we show that two lineages, 2.MED and 1.ORI3, spread significantly faster than others, possibly reflecting differences among strains in transmission mechanisms and virulence. Plague spread fastest in regions with low population density and high proportion of pasture- or forestland, findings that should be taken into account for effective plague monitoring and control. Temperature exhibited a nonlinear, U-shaped association with spread speed, with a minimum around 20 degrees C, while precipitation showed a positive association. Our results suggest that global warming may accelerate plague spread in warm, tropical regions and that the projected increased precipitation in the Northern Hemisphere may increase plague spread in relevant regions. |
High-quality health systems in the Sustainable Development Goals era: time for a revolution
Kruk ME , Gage AD , Arsenault C , Jordan K , Leslie HH , Roder-DeWan S , Adeyi O , Barker P , Daelmans B , Doubova SV , English M , Elorrio EG , Guanais F , Gureje O , Hirschhorn LR , Jiang L , Kelley E , Lemango ET , Liljestrand J , Malata A , Marchant T , Matsoso MP , Meara JG , Mohanan M , Ndiaye Y , Norheim OF , Reddy KS , Rowe AK , Salomon JA , Thapa G , Twum-Danso NAY , Pate M . Lancet Glob Health 2018 6 (11) e1196-e1252 Although health outcomes have improved in low-income and middle-income countries (LMICs) in the past several decades, a new reality is at hand. Changing health needs, growing public expectations, and ambitious new health goals are raising the bar for health systems to produce better health outcomes and greater social value. But staying on current trajectory will not suffice to meet these demands. What is needed are high-quality health systems that optimise health care in each given context by consistently delivering care that improves or maintains health, by being valued and trusted by all people, and by responding to changing population needs. Quality should not be the purview of the elite or an aspiration for some distant future; it should be the DNA of all health systems. Furthermore, the human right to health is meaningless without good quality care because health systems cannot improve health without it. |
Acquisition of Bartonella elizabethae by experimentally exposed oriental rat fleas (Xenopsylla cheopis; Siphonaptera, Pulicidae) and excretion of Bartonella DNA in flea feces
McKee CD , Osikowicz LM , Schwedhelm TR , Maes SE , Enscore RE , Gage KL , Kosoy MY . J Med Entomol 2018 55 (5) 1292-1298 Few studies have been able to provide experimental evidence of the ability of fleas to maintain rodent-associated Bartonella infections and excrete these bacteria. These data are important for understanding the transmission cycles and prevalence of these bacteria in hosts and vectors. We used an artificial feeding approach to expose groups of the oriental rat flea (Xenopsylla cheopis Rothschild; Siphonaptera, Pulicidae) to rat blood inoculated with varying concentrations of Bartonella elizabethae Daly (Bartonellaceae: Rhizobiales). Flea populations were maintained by membrane feeding on pathogen-free bloodmeals for up to 13 d post infection. Individual fleas and pools of flea feces were tested for the presence of Bartonella DNA using molecular methods (quantitative and conventional polymerase chain reaction [PCR]). The threshold number of Bartonellae required in the infectious bloodmeal for fleas to be detected as positive was 106 colony-forming units per milliliter (CFU/ml). Individual fleas were capable of harboring infections for at least 13 d post infection and continuously excreted Bartonella DNA in their feces over the same period. This experiment demonstrated that X. cheopis are capable of acquiring and excreting B. elizabethae over several days. These results will guide future work to model and understand the role of X. cheopis in the natural transmission cycle of rodent-borne Bartonella species. Future experiments using this artificial feeding approach will be useful for examining the horizontal transmission of B. elizabethae or other rodent-associated Bartonella species to naive hosts and for determining the viability of excreted bacteria. |
Drivers of flea (Siphonaptera) community structure in sympatric wild carnivores in northwestern Mexico
Lopez-Perez AM , Gage K , Rubio AV , Montenieri J , Orozco L , Suzan G . J Vector Ecol 2018 43 (1) 15-25 Host identity, habitat type, season, and interspecific interactions were investigated as determinants of the community structure of fleas on wild carnivores in northwestern Mexico. A total of 540 fleas belonging to seven species was collected from 64 wild carnivores belonging to eight species. We found that the abundances of some flea species are explained by season and host identity. Pulex irritans and Echidnophaga gallinacea abundances were significantly higher in spring than in fall season. Flea communities on carnivore hosts revealed three clusters with a high degree of similarity within each group that was explained by the flea dominance of E. gallinacea, P. simulans, and P. irritans across host identity. Flea abundances did not differ statistically among habitat types. Finally, we found a negative correlation between the abundances of three flea species within wild carnivore hosts. Individual hosts with high loads of P. simulans males usually had significantly lower loads of P. irritans males or tend to have lower loads of E. gallinacea fleas and vice-versa. Additionally, the logistic regression model showed that the presence of P. simulans males is more likely to occur in wild carnivore hosts in which P. irritans males are absent and vice-versa. These results suggest that there is an apparent competitive exclusion among fleas on wild carnivores. The study of flea community structure on wild carnivores is important to identify the potential flea vectors for infectious diseases and provide information needed to design programs for human health and wildlife conservation. |
An evaluation of removal trapping to control rodents inside homes in a plague-endemic region of rural Northwestern Uganda
Eisen RJ , Atiku LA , Boegler KA , Mpanga JT , Enscore RE , MacMillan K , Gage KL . Vector Borne Zoonotic Dis 2018 18 (9) 458-463 Rodents pose a significant threat to human health, particularly in rural subsistence farming communities in Africa, where rodents threaten food security and serve as reservoirs of human pathogens, including the agents of plague, leptospirosis, murine typhus, rat-bite fever, Lassa fever, salmonellosis, and campylobacteriosis. Our study focused on the plague-endemic West Nile region of Uganda, where a majority of residents live in Uganda government-defined poverty, rely on subsistence farming for a living, and frequently experience incursions of rodents into their homes. In this study, we show that rodent removal was achieved in a median of 6 days of intensive lethal trapping with multiple trap types (range: 0-16 days). However, rodent abundance in 68.9% of homesteads returned to pretreatment levels within a median of 8 weeks (range 1-24 weeks), and at least a single rodent was captured in all homesteads by a median of 2 weeks (range 1-16 weeks) after removal efforts were terminated. Results were similar between homesteads that practiced rodent control whether or not their neighbors implemented similar strategies. Overall, intensive lethal trapping inside homes appears to be effective at reducing rodent abundance, but control was short lived after trapping ceased. |
Mammalian hosts, vectors, and bacterial pathogens in communities with and without black-tailed prairie dogs (Cynomys ludovicianus) in northwestern Mexico
Zapata-Valdes C , Avila-Flores R , Gage K , Holmes J , Montenierri J , Kosoy M , Suzan G . J Wildl Dis 2018 54 (1) 26-33 The presence of keystone species can influence disease dynamics through changes in species diversity and composition of vector and host communities. In this study, we compared 1) the diversity of small mammals; 2) the prevalence, abundance, and intensity of arthropod vectors; and 3) the prevalence of Yersinia pestis, Francisella tularensis, and Bartonella spp. in vectors, between two grassland communities of northern Sonora, Mexico, one with (La Mesa [LM]) and one without (Los Fresnos [LF]) black-tailed prairie dogs ( Cynomys ludovicianus). The mammal community in LF exhibited higher species richness and diversity than LM, and species composition was different between the two communities. Flea species richness, prevalence, abundance, and intensity, were higher in LM than in LF. The most abundant fleas were Oropsylla hirsuta and Pulex simulans, and C. ludovicianus was the host with the highest flea intensity and richness. There was no serologic evidence for the presence of Y. pestis and F. tularensis in any community, but Bartonella spp. was present in 18% of the total samples. Some specificity was observed between Bartonella species, flea species, and mammal species. Although prairie dogs can indirectly affect the diversity and abundance of hosts and vectors, dynamics of vector-borne diseases at these spatial and temporal scales may be more dependent on the vector and pathogen specificity. |
Comparison of Zoonotic Bacterial Agents in Fleas Collected from Small Mammals or Host-Seeking Fleas from a Ugandan Region Where Plague Is Endemic.
Bai Y , Osikowicz LM , Kosoy MY , Eisen RJ , Atiku LA , Mpanga JT , Boegler KA , Enscore RE , Gage KL . mSphere 2017 2 (6) Fleas (n = 407) were collected from small mammals trapped inside huts and surroundings of homesteads in five villages within the Arua and Zombo districts of Uganda. The most common flea species were Dinopsyllus lypusus (26%) and Xenopsylla cheopis (50%). Off-host fleas (n = 225) were collected inside huts by using Kilonzo flea traps. The majority of the off-host fleas were Ctenocephalides felis (80%). All fleas were examined for the presence of Bartonella spp., Rickettsia spp., and Yersinia spp. Bartonella DNA was detected in 91 fleas, with an overall prevalence of 14%. Bartonella prevalence was significantly higher in rodent or shrew fleas than in off-host fleas (22% versus 1%). The majority of Bartonella-positive fleas were of the species D. lypusus (61%), X. cheopis (20%), and Ctenophthalmus calceatus (14%). Sequencing analysis identified 12 Bartonella genetic variants, 9 of which belonged to the zoonotic pathogen B. elizabethae species complex. Rickettsia DNA was detected in 143 fleas, giving an overall prevalence of 23%, with a significantly higher prevalence in off-host fleas than in rodent or shrew fleas (56% versus 4%). The majority (88%) of Rickettsia-positive fleas were C. felis and were collected from Kilonzo traps, while a small portion (10%) were X. cheopis collected from rodents. Sequencing analysis identified six Rickettsia genogroups that belonged either to zoonotic R. felis or to the closely related "Candidatus Ricksettia asemboensis" and "Candidatus Ricksettia sengalensis." Yersinia DNA was not detected in the fleas tested. These observations suggested that fleas in northwestern Uganda commonly carry the zoonotic agents B. elizabethae and R. felis and potentially play an important role in transmitting these infections to humans. IMPORTANCE Fleas play critical roles in transmitting some infections among animals and from animals to humans. Detection of pathogens in fleas is important to determine human risks for flea-borne diseases and can help guide diagnosis and treatment. Our findings of high prevalence rates of B. elizabethae and R. felis in fleas in the Arua and Zombo districts of Uganda implicate these agents as potential causative agents of undiagnosed febrile illnesses in this area. |
Rat fall surveillance coupled with vector control and community education as a plague prevention strategy in the West Nile Region, Uganda
Boegler KA , Atiku LA , Enscore RE , Apangu T , Mpanga JT , Acayo S , Kaggwa J , Mead PS , Yockey BM , Kugeler KJ , Schriefer ME , Horiuchi K , Gage KL , Eisen RJ . Am J Trop Med Hyg 2017 98 (1) 238-247 Plague, primarily a disease of rodents, is most frequently transmitted by fleas and causes potentially fatal infections in humans. In Uganda, plague is endemic to the West Nile region. Primary prevention for plague includes control of rodent hosts or flea vectors, but targeting these efforts is difficult given the sporadic nature of plague epizootics in the region and limited resource availability. Here, we present a community-based strategy to detect and report rodent deaths (rat fall), an early sign of epizootics. Laboratory testing of rodent carcasses is used to trigger primary and secondary prevention measures: indoor residual spraying (IRS) and community-based plague education, respectively. During the first 3 years of the program, individuals from 142 villages reported 580 small mammal deaths; 24 of these tested presumptive positive for Yersinia pestis by fluorescence microscopy. In response, for each of the 17 affected communities, village-wide IRS was conducted to control rodent-associated fleas within homes, and community sensitization was conducted to raise awareness of plague signs and prevention strategies. No additional presumptive Y. pestis-positive carcasses were detected in these villages within the 2-month expected duration of residual activity for the insecticide used in IRS. Despite comparatively high historic case counts, no human plague cases were reported from villages participating in the surveillance program; five cases were reported from elsewhere in the districts. We evaluate community participation and timeliness of response, report the frequency of human plague cases in participating and surrounding villages, and evaluate whether a program such as this could provide a sustainable model for plague prevention in endemic areas. |
Small-scale die-offs in woodrats support long-term maintenance of plague in the U.S. Southwest
Kosoy M , Reynolds P , Bai Y , Sheff K , Enscore RE , Montenieri J , Ettestad P , Gage K . Vector Borne Zoonotic Dis 2017 17 (9) 635-644 Our longitudinal study of plague dynamics was conducted in north-central New Mexico to identify which species in the community were infected with plague, to determine the spatial and temporal patterns of the dynamics of plague epizootics, and to describe the dynamics of Yersinia pestis infection within individual hosts. A total of 3156 fleas collected from 535 small mammals of 8 species were tested for Y. pestis DNA. Nine fleas collected from six southern plains woodrats (Neotoma micropus) and from one rock squirrel (Otospermophilus variegatus) were positive for the pla gene of Y. pestis. None of 127 fleas collected from 17 woodrat nests was positive. Hemagglutinating antibodies to the Y. pestis-specific F1 antigen were detected in 11 rodents of 6 species. All parts of the investigated area were subjected to local disappearance of woodrats. Despite the active die-offs, some woodrats always were present within the relatively limited endemic territory and apparently were never exposed to plague. Our observations suggest that small-scale die-offs in woodrats can support maintenance of plague in the active U.S. Southwestern focus. |
Metabolomics of the tick-Borrelia interaction during the nymphal tick blood meal
Hoxmeier JC , Fleshman AC , Broeckling CD , Prenni JE , Dolan MC , Gage KL , Eisen L . Sci Rep 2017 7 44394 The causal agents of Lyme disease in North America, Borrelia burgdorferi and Borrelia mayonii, are transmitted primarily by Ixodes scapularis ticks. Due to their limited metabolic capacity, spirochetes rely on the tick blood meal for nutrients and metabolic intermediates while residing in the tick vector, competing with the tick for nutrients in the blood meal. Metabolomics is an effective methodology to explore dynamics of spirochete survival and multiplication in tick vectors before transmission to a vertebrate host via tick saliva. Using gas chromatography coupled to mass spectrometry, we identified statistically significant differences in the metabolic profile among uninfected I. scapularis nymphal ticks, B. burgdorferi-infected nymphal ticks and B. mayonii-infected nymphal ticks by measuring metabolism every 24 hours over the course of their up to 96 hour blood meals. Specifically, differences in the abundance of purines, amino acids, carbohydrates, and fatty acids during the blood meal among the three groups of nymphal ticks suggest that B. mayonii and B. burgdorferi may have different metabolic capabilities, especially during later stages of nymphal feeding. Understanding mechanisms underlying variable metabolic requirements of different Lyme disease spirochetes within tick vectors could potentially aid development of novel methods to control spirochete transmission. |
Prevalence and Phylogenetic Analysis of Bartonella Species of Wild Carnivores and Their Fleas in Northwestern Mexico.
Lopez-Perez AM , Osikowicz L , Bai Y , Montenieri J , Rubio A , Moreno K , Gage K , Suzan G , Kosoy M . Ecohealth 2017 14 (1) 116-129 The host-parasite-vector relationship of Bartonella spp. system in wild carnivores and their fleas from northwestern Mexico was investigated. Sixty-six carnivores belonging to eight species were sampled, and 285 fleas belonging to three species were collected during spring (April-May) and fall (October-November) seasons. We detected Bartonella species in 7 carnivores (10.6%) and 27 fleas (9.5%) through either blood culture or PCR. Of the 27 Bartonella-positive fleas, twenty-two were Pulex simulans, three were Pulex irritans and one was Echidnophaga gallinacea. The gltA gene and ITS region sequences alignment revealed six and eight genetic variants of Bartonella spp., respectively. These variants were clustered into Bartonella rochalimae, Bartonella vinsonii subsp. berkhoffii and another genotype, which likely represents a novel species of Bartonella spp. Although experimental infection studies are required to prove the vector role of P. simulans, our results suggest that this flea may play an important role in the Bartonella transmission. The results indicated possible host-specific relationships between Bartonella genotypes and the families of the carnivores, but further studies are needed to verify this finding. The presence of zoonotic species of Bartonella spp. in wild carnivores raises the issue of their potential risk for humans in fragmented ecosystems. |
Droughts may increase susceptibility of prairie dogs to fleas: Incongruity with hypothesized mechanisms of plague cycles in rodents
Eads DA , Biggins DE , Long DH , Gage KL , Antolin MF . J Mammal 2016 97 (4) 1044-1053 Plague is a reemerging, rodent-associated zoonosis caused by the flea-borne bacterium Yersinia pestis. As a vector-borne disease, rates of plague transmission may increase when fleas are abundant. Fleas are highly susceptible to desiccation under hot-dry conditions; we posited that their densities decline during droughts. We evaluated this hypothesis with black-tailed prairie dogs (Cynomys ludovicianus) in New Mexico, June-August 2010-2012. Precipitation was relatively plentiful during 2010 and 2012 but scarce during 2011, the driest spring-summer on record for the northeastern grasslands of New Mexico. Unexpectedly, fleas were 200% more abundant in 2011 than in 2010 and 2012. Prairie dogs were in 27% better condition during 2010 and 2012, and they devoted 287% more time to grooming in 2012 than in 2011. During 2012, prairie dogs provided with supplemental food and water were in 23% better condition and carried 40% fewer fleas. Collectively, these results suggest that during dry years, prairie dogs are limited by food and water, and they exhibit weakened defenses against fleas. Long-term data are needed to evaluate the generality of whether droughts increase flea densities and how changes in flea abundance during sequences of dry and wet years might affect plague cycles in mammalian hosts. |
Ecological traits driving the outbreaks and emergence of zoonotic pathogens
Salkeld DJ , Stapp P , Tripp DW , Gage KL , Lowell J , Webb CT , Brinkerhoff RJ , Antolin MF . BioScience 2016 66 (2) 118-129 Infectious diseases that are transmitted from wildlife hosts to humans, such as the Ebola virus and MERS virus, can be difficult to understand because the pathogens emerge from complex multifaceted ecological interactions. We use a wildlife-pathogen system - prairie dogs (Cynomys ludovicianus) and the plague bacterium (Yersinia pestis) - to describe aspects of disease ecology that apply to many cases of emerging infectious disease. We show that the monitoring and surveillance of hosts and vectors during the buildup to disease outbreaks are crucial for understanding pathogen-transmission dynamics and that a community-ecology framework is important to identify reservoir hosts. Incorporating multidisciplinary approaches and frameworks may improve wildlife-pathogen surveillance and our understanding of seemingly sporadic and rare pathogen outbreaks. |
World Health Organization guidelines for treatment of cervical intraepithelial neoplasia 2-3 and screen-and-treat strategies to prevent cervical cancer
Santesso N , Mustafa RA , Schunemann HJ , Arbyn M , Blumenthal PD , Cain J , Chirenje M , Denny L , De Vuyst H , Eckert LO , Forhan SE , Franco EL , Gage JC , Garcia F , Herrero R , Jeronimo J , Lu ER , Luciani S , Quek SC , Sankaranarayanan R , Tsu V , Broutet N . Int J Gynaecol Obstet 2015 132 (3) 252-8 BACKGROUND: It is estimated that 1%-2% of women develop cervical intraepithelial neoplasia grade 2-3 (CIN 2-3) annually worldwide. The prevalence among women living with HIV is higher, at 10%. If left untreated, CIN 2-3 can progress to cervical cancer. WHO has previously published guidelines for strategies to screen and treat precancerous cervical lesions and for treatment of histologically confirmed CIN 2-3. METHODS: Guidelines were developed using the WHO Handbook for Guideline Development and the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. A multidisciplinary guideline panel was created. Systematic reviews of randomized controlled trials and observational studies were conducted. Evidence tables and Evidence to Recommendations Tables were prepared and presented to the panel. RESULTS: There are nine recommendations for screen-and-treat strategies to prevent cervical cancer, including the HPV test, cytology, and visual inspection with acetic acid. There are seven for treatment of CIN with cryotherapy, loop electrosurgical excision procedure, and cold knife conization. CONCLUSION: Recommendations have been produced on the basis of the best available evidence. However, high-quality evidence was not available. Such evidence is needed, in particular for screen-and-treat strategies that are relevant to low- and middle-income countries. |
Seasonal fluctuations of small mammal and flea communities in a Ugandan plague focus: evidence to implicate Arvicanthis niloticus and Crocidura spp. as key hosts in Yersinia pestis transmission
Moore SM , Monaghan A , Borchert JN , Mpanga JT , Atiku LA , Boegler KA , Montenieri J , MacMillan K , Gage KL , Eisen RJ . Parasit Vectors 2015 8 11 BACKGROUND: The distribution of human plague risk is strongly associated with rainfall in the tropical plague foci of East Africa, but little is known about how the plague bacterium is maintained during periods between outbreaks or whether environmental drivers trigger these outbreaks. We collected small mammals and fleas over a two year period in the West Nile region of Uganda to examine how the ecological community varies seasonally in a region with areas of both high and low risk of human plague cases. METHODS: Seasonal changes in the small mammal and flea communities were examined along an elevation gradient to determine whether small mammal and flea populations exhibit differences in their response to seasonal fluctuations in precipitation, temperature, and crop harvests in areas within (above 1300 m) and outside (below 1300 m) of a model-defined plague focus. RESULTS: The abundance of two potential enzootic host species (Arvicanthis niloticus and Crocidura spp.) increased during the plague season within the plague focus, but did not show the same increase at lower elevations outside this focus. In contrast, the abundance of the domestic rat population (Rattus rattus) did not show significant seasonal fluctuations regardless of locality. Arvicanthis niloticus abundance was negatively associated with monthly precipitation at a six month lag and positively associated with current monthly temperatures, and Crocidura spp. abundance was positively associated with precipitation at a three month lag and negatively associated with current monthly temperatures. The abundance of A. niloticus and Crocidura spp. were both positively correlated with the harvest of millet and maize. CONCLUSIONS: The association between the abundance of several small mammal species and rainfall is consistent with previous models of the timing of human plague cases in relation to precipitation in the West Nile region. The seasonal increase in the abundance of key potential host species within the plague focus, but not outside of this area, suggests that changes in small mammal abundance may create favorable conditions for epizootic transmission of Y. pestis which ultimately may increase risk of human cases in this region. |
Molecular Survey of Bartonella Species and Yersinia pestis in Rodent Fleas (Siphonaptera) From Chihuahua, Mexico.
Fernandez-Gonzalez AM , Kosoy MY , Rubio AV , Graham CB , Montenieri JA , Osikowicz LM , Bai Y , Acosta-Gutierrez R , Avila-Flores R , Gage KL , Suzan G . J Med Entomol 2015 53 (1) 199-205 Rodent fleas from northwestern Chihuahua, Mexico, were analyzed for the presence of Bartonella and Yersinia pestis. In total, 760 fleas belonging to 10 species were tested with multiplex polymerase chain reaction analysis targeting the gltA (338-bp) and pla genes (478-bp) of Bartonella and Y. pestis, respectively. Although none was positive for Y. pestis, 307 fleas were infected with Bartonella spp., resulting in an overall prevalence of 40.4%. A logistic regression analysis indicated that the presence of Bartonella is more likely to occur in some flea species. From a subset of Bartonella-positive fleas, phylogenetic analyses of gltA gene sequences revealed 13 genetic variants clustering in five phylogroups (I-V), two of which were matched with known pathogenic Bartonella species (Bartonella vinsonii subsp. arupensis and Bartonella washoensis) and two that were not related with any previously described species or subspecies of Bartonella. Variants in phylogroup V, which were mainly obtained from Meringis spp. fleas, were identical to those reported recently in their specific rodent hosts (Dipodomys spp.) in the same region, suggesting that kangaroo rats and their fleas harbor other Bartonella species not reported previously. Considering the Bartonella prevalence and the flea genotypes associated with known pathogenic Bartonella species, we suggest that analysis of rodent and flea communities in the region should continue for their potential implications for human health. Given that nearby locations in the United States have reported Y. pestis in wild animals and their fleas, we suggest conducting larger-scale studies to increase our knowledge of this bacterium. |
Flea-associated bacterial communities across an environmental transect in a plague-endemic region of Uganda
Jones RT , Borchert J , Eisen R , MacMillan K , Boegler K , Gage KL . PLoS One 2015 10 (10) e0141057 The vast majority of human plague cases currently occur in sub-Saharan Africa. The primary route of transmission of Yersinia pestis, the causative agent of plague, is via flea bites. Non-pathogenic flea-associated bacteria may interact with Y. pestis within fleas and it is important to understand what factors govern flea-associated bacterial assemblages. Six species of fleas were collected from nine rodent species from ten Ugandan villages between October 2010 and March 2011. A total of 660,345 16S rRNA gene DNA sequences were used to characterize bacterial communities of 332 individual fleas. The DNA sequences were binned into 421 Operational Taxonomic Units (OTUs) based on 97% sequence similarity. We used beta diversity metrics to assess the effects of flea species, flea sex, rodent host species, site (i.e. village), collection date, elevation, mean annual precipitation, average monthly precipitation, and average monthly temperature on bacterial community structure. Flea species had the greatest effect on bacterial community structure with each flea species harboring unique bacterial lineages. The site (i.e. village), rodent host, flea sex, elevation, precipitation, and temperature also significantly affected bacterial community composition. Some bacterial lineages were widespread among flea species (e.g. Bartonella spp. and Wolbachia spp.), but each flea species also harbored unique bacterial lineages. Some of these lineages are not closely related to known bacterial diversity and likely represent newly discovered lineages of insect symbionts. Our finding that flea species has the greatest effect on bacterial community composition may help future investigations between Yersinia pestis and non-pathogenic flea-associated bacteria. Characterizing bacterial communities of fleas during a plague epizootic event in the future would be helpful. |
The role of early-phase transmission in the spread of Yersinia pestis
Eisen RJ , Dennis DT , Gage KL . J Med Entomol 2015 52 (6) 1183-92 Early-phase transmission (EPT) of Yersinia pestis by unblocked fleas is a well-documented, replicable phenomenon with poorly defined mechanisms. We review evidence demonstrating EPT and current knowledge on its biological and biomechanical processes. We discuss the importance of EPT in the epizootic spread of Y. pestis and its role in the maintenance of plague bacteria in nature. We further address the role of EPT in the epidemiology of plague. |
Human plague - United States, 2015
Kwit N , Nelson C , Kugeler K , Petersen J , Plante L , Yaglom H , Kramer V , Schwartz B , House J , Colton L , Feldpausch A , Drenzek C , Baumbach J , DiMenna M , Fisher E , Debess E , Buttke D , Weinburke M , Percy C , Schriefer M , Gage K , Mead P . MMWR Morb Mortal Wkly Rep 2015 64 (33) 918-919 Since April 1, 2015, a total of 11 cases of human plague have been reported in residents of six states: Arizona (two), California (one), Colorado (four), Georgia (one), New Mexico (two), and Oregon (one). The two cases in Georgia and California residents have been linked to exposures at or near Yosemite National Park in the southern Sierra Nevada Mountains of California. Nine of the 11 patients were male; median age was 52 years (range = 14-79 years). Three patients aged 16, 52, and 79 years died. |
Single-Nucleotide Polymorphisms Reveal Spatial Diversity Among Clones of Yersinia pestis During Plague Outbreaks in Colorado and the Western United States.
Lowell JL , Antolin MF , Andersen GL , Hu P , Stokowski RP , Gage KL . Vector Borne Zoonotic Dis 2015 15 (5) 291-302 BACKGROUND: In western North America, plague epizootics caused by Yersinia pestis appear to sweep across landscapes, primarily infecting and killing rodents, especially ground squirrels and prairie dogs. During these epizootics, the risk of Y. pestis transmission to humans is highest. While empirical models that include climatic conditions and densities of rodent hosts and fleas can predict when epizootics are triggered, bacterial transmission patterns across landscapes, and the scale at which Y. pestis is maintained in nature during inter-epizootic periods, are poorly defined. Elucidating the spatial extent of Y. pestis clones during epizootics can determine whether bacteria are propagated across landscapes or arise independently from local inter-epizootic maintenance reservoirs. MATERIAL AND METHODS: We used DNA microarray technology to identify single-nucleotide polymorphisms (SNPs) in 34 Y. pestis isolates collected in the western United States from 1980 to 2006, 21 of which were collected during plague epizootics in Colorado. Phylogenetic comparisons were used to elucidate the hypothesized spread of Y. pestis between the mountainous Front Range and the eastern plains of northern Colorado during epizootics. Isolates collected from across the western United States were included for regional comparisons. RESULTS: By identifying SNPs that mark individual clones, our results strongly suggest that Y. pestis is maintained locally and that widespread epizootic activity is caused by multiple clones arising independently at small geographic scales. This is in contrast to propagation of individual clones being transported widely across landscapes. Regionally, our data are consistent with the notion that Y. pestis diversifies at relatively local scales following long-range translocation events. We recommend that surveillance and prediction by public health and wildlife management professionals focus more on models of local or regional weather patterns and ecological factors that may increase risk of widespread epizootics, rather than predicting or attempting to explain epizootics on the basis of movement of host species that may transport plague. |
Epidemiology of human plague in the United States, 1900-2012
Kugeler KJ , Staples JE , Hinckley AF , Gage KL , Mead PS . Emerg Infect Dis 2015 21 (1) 16-22 We summarize the characteristics of 1,006 cases of human plague occurring in the United States over 113 years, beginning with the first documented case in 1900. Three distinct eras can be identified on the basis of the frequency, nature, and geographic distribution of cases. During 1900-1925, outbreaks were common but were restricted to populous port cities. During 1926-1964, the geographic range of disease expanded rapidly, while the total number of reported cases fell. During 1965-2012, sporadic cases occurred annually, primarily in the rural Southwest. Clinical and demographic features of human illness have shifted over time as the disease has moved from crowded cities to the rural West. These shifts reflect changes in the populations at risk, the advent of antibiotics, and improved detection of more clinically indistinct forms of infection. Overall, the emergence of human plague in the United States parallels observed patterns of introduction of exotic plants and animals. |
LPS modification promotes maintenance of Yersinia pestis in fleas.
Aoyagi K , Brooks BD , Bearden SW , Montenieri JA , Gage KL , Fisher MA . Microbiology (Reading) 2014 161 628-38 Yersinia pestis, the causative agent of plague, can be transmitted by fleas in two different manners: by early phase transmission (EPT), which occurs shortly after flea infection, or by blocked fleas following long-term infection. Efficient flea-borne transmission is predicated upon the ability of Y. pestis to be maintained within the flea. Signature-tagged mutagenesis (STM) was used to identify genes required for Y. pestis maintenance in a genuine plague vector, Xenopsylla cheopis. The STM screen identified seven mutants that displayed markedly reduced fitness in fleas after four days, the time during which EPT occurs. Two of the mutants contained insertions in genes encoding glucose-1-phosphate uridylyltransferase (galU) and UDP-4-amino-4-deoxy-L-arabinose-oxoglutarate aminotransferase (arnB), which are involved in the modification of lipid A with aminoarabinose (Ara4N) and resistance to cationic antimicrobial peptides (CAMPs). These Y. pestis mutants were more susceptible to the CAMPs cecropin A and polymyxin B, and produced lipid A lacking Ara4N modifications. Surprisingly, an in-frame deletion of arnB retained modest levels of CAMP resistance and Ara4N modification, indicating the presence of compensatory factors. It was determined that WecE, an aminotransferase involved in biosynthesis of enterobacterial common antigen, plays a novel role in Y. pestis Ara4N modification by partially offsetting the loss of arnB. These results indicate that mechanisms of Ara4N modification of lipid A are more complex than previously thought, and these modifications, as well as several factors yet to be elucidated, play an important role in early survival and transmission of Y. pestis in the flea vector. |
Evaluation of the effect of host immune status on short-term Yersinia pestis infection in fleas with implications for the enzootic host model for maintenance of Y. pestis during interepizootic periods
Graham CB , Woods ME , Vetter SM , Petersen JM , Montenieri JA , Holmes JL , Maes SE , Bearden SW , Gage KL , Eisen RJ . J Med Entomol 2014 51 (5) 1079-1086 Plague, a primarily flea-borne disease caused by Yersinia pestis, is characterized by rapidly spreading epizootics separated by periods of quiescence. Little is known about how and where Y. pestis persists between epizootics. It is commonly proposed, however, that Y. pestis is maintained during interepizootic periods in enzootic cycles involving flea vectors and relatively resistant host populations. According to this model, while susceptible individuals serve as infectious sources for feeding fleas and subsequently die of infection, resistant hosts survive infection, develop antibodies to the plague bacterium, and continue to provide bloodmeals to infected fleas. For Y. pestis to persist under this scenario, fleas must remain infected after feeding on hosts carrying antibodies to Y. pestis. Studies of other vector-borne pathogens suggest that host immunity may negatively impact pathogen survival in the vector. Here, we report infection rates and bacterial loads for fleas (both Xenopsylla cheopis (Rothschild) and Oropsylla montana (Baker)) that consumed an infectious bloodmeal and subsequently fed on an immunized or age-matched naive mouse. We demonstrate that neither the proportion of infected fleas nor the bacterial loads in infected fleas were significantly lower within 3 d of feeding on immunized versus naive mice. Our findings thus provide support for one assumption underlying the enzootic host model of interepizootic maintenance of Y. pestis. |
Yersinia murine toxin is not required for early-phase transmission of Yersinia pestis by Oropsylla montana (siphonaptera: ceratophyllidae) or Xenopsylla cheopis (siphonaptera: pulicidae)
Johnson TL , Hinnebusch BJ , Boegler KA , Graham CB , MacMillian K , Montenieri JA , Bearden SW , Gage KL , Eisen RJ . Microbiology (Reading) 2014 160 2517-2525 Plague, caused by Yersinia pestis, is characterized by quiescent periods punctuated by rapidly spreading epizootics. The classical "blocked flea" paradigm, by which a blockage forms in the flea's proventriculus on average 1-2 weeks post infection, forces starving fleas to take multiple blood meals, thus increasing opportunities for transmission. Recently the importance of early-phase transmission (EPT), which occurs prior to blockage formation, has been emphasized during epizootics. While the physiological and molecular mechanisms of blocked flea transmission are well characterized, the pathogen-vector interactions have not been elucidated for EPT. Within the blocked flea model, Yersinia murine toxin (Ymt) has been shown to be important for facilitating colonization of the midgut within the flea. One proposed mechanism of EPT is the regurgitation of infectious material from the flea midgut during feeding. Such a mechanism would require bacteria to colonize and survive for at least brief periods in the midgut, a process that is mediated by Ymt. Two key bridging vectors of Y. pestis to humans, Oropsylla montana and Xenopsylla cheopis, were used in our study to test this hypothesis. Fleas were infected with a mutant strain of Y. pestis containing a nonfunctional ymt that was previously shown to be incapable of colonizing the midgut, and were then allowed to feed on SKH-1 mice 3 days post infection. Our results show that Ymt is not required for EPT by either flea species. |
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