Last data update: Apr 22, 2024. (Total: 46599 publications since 2009)
Records 1-30 (of 36 Records) |
Query Trace: McElroy AK [original query] |
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Marburgvirus resurgence in Kitaka Mine bat population after extermination attempts, Uganda.
Amman BR , Nyakarahuka L , McElroy AK , Dodd KA , Sealy TK , Schuh AJ , Shoemaker TR , Balinandi S , Atimnedi P , Kaboyo W , Nichol ST , Towner JS . Emerg Infect Dis 2014 20 (10) 1761-4 Marburg virus (MARV) and Ravn virus (RAVV), collectively called marburgviruses, cause Marburg hemorrhagic fever (MHF) in humans. In July 2007, 4 cases of MHF (1 fatal) occurred in miners at Kitaka Mine in southern Uganda. Later, MHF occurred in 2 tourists who visited Python Cave, ≈50 km from Kitaka Mine. One of the tourists was from the United States (December 2007) and 1 was from the Netherlands (July 2008); 1 case was fatal (1,2,3). The cave and the mine each contained 40,000–100,000 Rousettus aegyptiacus bats (Egyptian fruit bats). | | Longitudinal investigations of the outbreaks at both locations were initiated by the Viral Special Pathogens Branch of the Centers for Disease Control and Prevention (CDC, Atlanta, GA, USA, and Entebbe, Uganda) in collaboration with the Uganda Wildlife Authority (UWA) and the Uganda Virus Research Institute (UVRI). During these studies, genetically diverse MARVs and RAVVs were isolated directly from bat tissues, and infection levels of the 2 viruses were found to increase in juvenile bats on a predictable bi-annual basis (4,5). However, investigations at Kitaka Mine were stopped when the miners exterminated the bat colony by restricting egress from the cave with papyrus reed barriers and then entangling the bats in fishing nets draped over the exits. The trapping continued for weeks, and the entrances were then sealed with sticks and plastic. These depopulation efforts were documented by researchers from UVRI, the CDC, the National Institute of Communicable Diseases (Sandringham, South Africa), and UWA during site visits to Kitaka Mine (Technical Appendix Figure). In August 2008, thousands of dead bats were found piled in the forest, and by November 2008, there was no evidence of bats living in the mine; whether 100% extermination was achieved is unknown. CDC, UVRI, and UWA recommended against extermination, believing that any results would be temporary and that such efforts could exacerbate the problem if bat exclusion methods were not complete and permanent (6,7). |
Identification and characterization of Rift Valley fever virus-specific T cells reveals a dependence on CD40/CD40L interactions for prevention of encephalitis
Barbeau DJ , Cartwright HN , Harmon JR , Spengler JR , Spiropoulou CF , Sidney J , Sette A , McElroy AK . J Virol 2021 95 (23) Jvi0150621 Rift Valley fever virus (RVFV) is an arbovirus found throughout Africa. It causes disease that is typically mild and self-limiting; however, some infected individuals experience severe manifestations, including hepatitis, encephalitis, or even death. Reports of RVFV encephalitis are notable amongst immunosuppressed individuals, suggesting a role for adaptive immunity in preventing this severe complication. This phenomenon has been modeled in C57BL/6 mice depleted of CD4 T cells prior to infection with DelNSs RVFV (RVFV containing a deletion of NSs), resulting in late-onset encephalitis accompanied by high levels of viral RNA in the brain in 30% of animals. In this study, we sought to define the specific type(s) of CD4 T cells that mediate protection from RVFV encephalitis. The viral epitopes targeted by CD4 and CD8 T cells were defined in C57BL/6 mice, and tetramers for both CD4 and CD8 T cells were generated. RVFV-specific CD8 T cells were expanded and of a cytotoxic and proliferating phenotype in the liver following infection. RVFV-specific CD4 T cells were identified in the liver and spleen following infection and phenotyped as largely Th1 or Tfh subtypes. Knock-out mice lacking various aspects of pathways important in Th1 and Tfh development and function were used to demonstrate that T-bet, CD40, CD40L, and MHCII mediated protection from RVFV encephalitis, while IFN-γ and IL-12 were dispensable. Virus-specific antibody responses correlated with protection from encephalitis in all mouse strains, suggesting that Tfh-B cell interactions modulate clinical outcome in this model. Importance: The prevention of RVFV encephalitis requires intact adaptive immunity. In this study we develop reagents to detect RVFV-specific T cells and provide evidence for Tfh cells and CD40/CD40L interactions as critical mediators of this protection. |
Immunologic timeline of Ebola virus disease and recovery in humans
McElroy AK , Akondy RS , McLlwain DR , Chen H , Bjornson-Hooper Z , Mukherjee N , Mehta AK , Nolan G , Nichol ST , Spiropoulou CF . JCI Insight 2020 5 (10) A complete understanding of human immune responses to Ebola virus infection is limited by the availability of specimens and the requirement for biosafety level 4 (BSL-4) containment. In an effort to bridge this gap, we evaluated cryopreserved PBMCs from 4 patients who survived Ebola virus disease (EVD) using an established mass cytometry antibody panel to characterize various cell populations during both the acute and convalescent phases. Acute loss of nonclassical monocytes and myeloid DCs, especially CD1c+ DCs, was noted. Classical monocyte proliferation and CD38 upregulation on plasmacytoid DCs coincided with declining viral load. Unsupervised analysis of cell abundance demonstrated acute declines in monocytic, NK, and T cell populations, but some populations, many of myeloid origin, increased in abundance during the acute phase, suggesting emergency hematopoiesis. Despite cell losses during the acute phase, upregulation of Ki-67 correlated with recovery of cell populations over time. These data provide insights into the human immune response during EVD. |
Rift Valley fever virus vaccination induces long-lived, antigen-specific human T cell responses
Harmon JR , Barbeau DJ , Nichol ST , Spiropoulou CF , McElroy AK . NPJ Vaccines 2020 5 (1) 17 Rift Valley fever virus (RVFV) is a zoonotic arbovirus of clinical significance in both livestock and humans. A formalin-inactivated virus preparation was initially developed for human use and tested in laboratory workers in the 1960s. Vaccination resulted in generation of neutralizing antibody titers in most recipients, but neutralization titers waned over time, necessitating frequent booster doses. In this study, T cell-based immune responses to the formalin-inactivated vaccine were examined in a cohort of seven individuals who received between 1 and 6 doses of the vaccine. RVFV-specific T cell responses were detectable up to 24 years post vaccination. Peripheral blood mononuclear cells from this cohort of individuals were used to map out the viral epitopes targeted by T cells in humans. These data provide tools for assessing human RVFV-specific T cell responses and are thus a valuable resource for future human RVFV vaccine efforts. |
Fluorescent Crimean-Congo hemorrhagic fever virus illuminates tissue tropism patterns and identifies early mononuclear phagocytic cell targets in IFNAR-/- mice
Welch SR , Ritter JM , McElroy AK , Harmon JR , Coleman-McCray JD , Scholte FEM , Kobinger GP , Bergeron E , Zaki SR , Nichol ST , Spengler JR , Spiropoulou CF . PLoS Pathog 2019 15 (12) e1008183 Crimean-Congo hemorrhagic fever virus (CCHFV, order Bunyavirales, family Nairoviridae, genus Orthonairovirus) is the tick-borne etiological agent of Crimean-Congo hemorrhagic fever (CCHF) in humans. Animals are generally susceptible to CCHFV infection but refractory to disease. Small animal models are limited to interferon-deficient mice, that develop acute fatal disease following infection. Here, using a ZsGreen1- (ZsG) expressing reporter virus (CCHFV/ZsG), we examine tissue tropism and dissemination of virus in interferon-alpha/beta receptor knock-out (Ifnar-/-) mice. We demonstrate that CCHFV/ZsG retains in vivo pathogenicity comparable to wild-type virus. Interestingly, despite high levels of viral RNA in all organs assessed, 2 distribution patterns of infection were observed by both fluorescence and immunohistochemistry (IHC), corresponding to the permissiveness of organ tissues. To further investigate viral dissemination and to temporally define cellular targets of CCHFV in vivo, mice were serially euthanized at different stages of disease. Flow cytometry was used to characterize CCHFV-associated alterations in hematopoietic cell populations and to classify infected cells in the blood, lymph node, spleen, and liver. ZsG signal indicated that mononuclear phagocytic cells in the lymphatic tissues were early targets of infection; in late-stage infection, overall, the highest levels of signal were detected in the liver, and ZsG was found in both antigen-presenting and lymphocyte cell populations. |
Longitudinal analysis of the human B cell response to Ebola virus infection
Davis CW , Jackson KJL , McElroy AK , Halfmann P , Huang J , Chennareddy C , Piper AE , Leung Y , Albarino CG , Crozier I , Ellebedy AH , Sidney J , Sette A , Yu T , Nielsen SCA , Goff AJ , Spiropoulou CF , Saphire EO , Cavet G , Kawaoka Y , Mehta AK , Glass PJ , Boyd SD , Ahmed R . Cell 2019 177 (6) 1566-1582 e17 Ebola virus (EBOV) remains a public health threat. We performed a longitudinal study of B cell responses to EBOV in four survivors of the 2014 West African outbreak. Infection induced lasting EBOV-specific immunoglobulin G (IgG) antibodies, but their subclass composition changed over time, with IgG1 persisting, IgG3 rapidly declining, and IgG4 appearing late. Striking changes occurred in the immunoglobulin repertoire, with massive recruitment of naive B cells that subsequently underwent hypermutation. We characterized a large panel of EBOV glycoprotein-specific monoclonal antibodies (mAbs). Only a small subset of mAbs that bound glycoprotein by ELISA recognized cell-surface glycoprotein. However, this subset contained all neutralizing mAbs. Several mAbs protected against EBOV disease in animals, including one mAb that targeted an epitope under evolutionary selection during the 2014 outbreak. Convergent antibody evolution was seen across multiple donors, particularly among VH3-13 neutralizing antibodies specific for the GP1 core. Our study provides a benchmark for assessing EBOV vaccine-induced immunity. |
Macrophage activation marker soluble CD163 associated with fatal and severe Ebola virus disease in humans
McElroy AK , Shrivastava-Ranjan P , Harmon JR , Martines RB , Silva-Flannery L , Flietstra TD , Kraft CS , Mehta AK , Lyon GM , Varkey JB , Ribner BS , Nichol ST , Zaki SR , Spiropoulou CF . Emerg Infect Dis 2019 25 (2) 290-298 Ebola virus disease (EVD) is associated with elevated cytokine levels, and hypercytokinemia is more pronounced in fatal cases. This type of hyperinflammatory state is reminiscent of 2 rheumatologic disorders known as macrophage activation syndrome and hemophagocytic lymphohistiocytosis, which are characterized by macrophage and T-cell activation. An evaluation of 2 cohorts of patients with EVD revealed that a marker of macrophage activation (sCD163) but not T-cell activation (sCD25) was associated with severe and fatal EVD. Furthermore, substantial immunoreactivity of host tissues to a CD163-specific antibody, predominantly in areas of extensive immunostaining for Ebola virus antigens, was observed in fatal cases. These data suggest that host macrophage activation contributes to EVD pathogenesis and that directed antiinflammatory therapies could be beneficial in the treatment of EVD. |
Adaptive immune responses in humans during Nipah virus acute and convalescent phases of infection
Arunkumar G , Devadiga S , McElroy AK , Prabhu S , Sheik S , Abdulmajeed J , Robin S , Sushama A , Jayaram A , Nittur S , Shakir M , Kumar KGS , Radhakrishnan C , Sakeena K , Vasudevan J , Reena KJ , Sarita RL , Klena JD , Spiropoulou CF , Laserson KF , Nichol ST . Clin Infect Dis 2019 69 (10) 1752-1756 Background: Nipah virus (NiV) is one of ten potential causes of imminent public health emergencies of international concern. We investigated the NiV outbreak that occurred in May 2018 in Kerala, India. Here we describe the longitudinal characteristics of cell-mediated and humoral immune responses to NiV infection during the acute and convalescent phases in two human survivors. Methods: Serial blood samples were obtained from the only two survivors of the NiV outbreak in Kerala. We used flow cytometry to determine the absolute T lymphocyte and B lymphocyte counts and the phenotypes of both T and B cells. We also detected and quantitated the humoral immune response to NiV by virus-specific IgM and IgG ELISA. Results: Absolute numbers of T lymphocytes remained within normal limits throughout the period of illness studied in both survivors. However, a marked elevation of activated CD8 T cells was observed in both cases. Over 30% of total CD8 T cells expressed Ki67, indicating active proliferation. Proliferating (Ki-67+) CD8 T cells expressed high levels of granzyme B and PD-1, consistent with the profile of acute effector cells. Total B lymphocyte, activated B cell, and plasmablast counts were also elevated in NiV survivors. These individuals developed detectable NiV-specific IgM and IgG antibodies within a week of disease onset. Clearance of NiV RNA from blood preceded the appearance of virus-specific IgG and coincided with the peak of activated CD8 T cells. Conclusion: We describe for the first time longitudinal kinetic data on the activation status of human B and T cell populations during acute Nipah virus infection. While marked CD8 T cell activation was observed with effector characteristics, activated CD4 T cells were less prominent. |
CD4 T cells, CD8 T cells, and monocytes coordinate to prevent Rift Valley fever virus encephalitis
Harmon JR , Spengler JR , Coleman-McCray JD , Nichol ST , Spiropoulou CF , McElroy AK . J Virol 2018 92 (24) Rift Valley fever virus (RVFV) is an arbovirus that causes disease in livestock and humans in Africa and the Middle East. While human disease is typically mild and self-limiting, some individuals develop severe manifestations, such as hepatitis, hemorrhagic fever or encephalitis. Encephalitis occurs 2-3 weeks after acute illness; therefore, we hypothesized that it was a result of an inadequate adaptive immunity. To test this hypothesis in vivo, we used an attenuated virus (DelNSsRVFV) that does not typically cause disease in mice. We first characterized the normal immune response to infection with DelNSsRVFV in immune-competent mice and noted expansion of natural killer cells and monocytes, as well as activation of both CD8 and CD4 T cells. Depleting C57BL/6 mice of CD4 T cells prior to DelNSsRVFV infection resulted in encephalitis in 30% of the mice; in encephalitic mice, we noted infiltration of T cells and inflammatory monocytes into the brain. CD4 and CD8 co-depletion in C57Bl/6 mice, as well as CD4 depletion in CCR2 knock-out mice increased the frequency of encephalitis, demonstrating that these cell types normally contributed to the prevention of disease. Encephalitic mice had similar viral RNA loads in the brain regardless of which cell types were depleted, suggesting that CD4 T cells, CD8 T cells, and inflammatory monocytes did little to control viral replication in the brain. CD4-depleted mice exhibited diminished humoral and T cell memory responses, suggesting that these immune mechanisms contributed to peripheral control of virus, thus preventing infection of the brain.Importance:RVFV is found in Africa and the Middle East and is transmitted by mosquitos or through contact with infected animals. Infected individuals can develop mild disease or more severe forms such as hepatitis or encephalitis. In order to understand why some individuals develop encephalitis, we first need to know which immune functions protect those who do not develop this form of disease. In this study, we used a mouse model of RVFV infection to demonstrate that CD4 T cells, CD8 T cells, and monocytes all contribute to prevention of encephalitis. Their likely mechanism of action is preventing RVFV from ever reaching the brain. |
Human immune cell engraftment does not alter development of severe acute Rift Valley fever in mice
Spengler JR , McElroy AK , Harmon JR , Coleman-McCray JD , Welch SR , Keck JG , Nichol ST , Spiropoulou CF . PLoS One 2018 13 (7) e0201104 Rift Valley fever (RVF) in humans is usually mild, but, in a subset of cases, can progress to severe hepatic and neurological disease. Rodent models of RVF generally develop acute severe clinical disease. Here, we inoculated humanized NSG-SGM3 mice with Rift Valley fever virus (RVFV) to investigate whether the presence of human immune cells in mice would alter the progression of RVFV infection to more closely model human disease. Despite increased human cytokine expression, including responses mirroring those seen in human disease, and decreased hepatic viral RNA levels at terminal euthanasia, both high- and low-dose RVFV inoculation resulted in lethal disease in all mice with comparable time-to-death as unengrafted mice. |
Human biomarkers of outcome following Rift valley fever virus infection
McElroy AK , Harmon JR , Flietstra T , Nichol ST , Spiropoulou CF . J Infect Dis 2018 218 (11) 1847-1851 Rift Valley fever virus is an arbovirus found in Africa and the Middle East. Most infected individuals experience a mild self-limiting illness; however, some develop severe disease including hepatitis, hemorrhagic fever, or encephalitis. The biological reasons for these marked differences in disease manifestation are unknown. In this study, we evaluate 32 biomarkers in serum of 26 patients from an outbreak that occurred in Saudi Arabia in 2000-2001. Eleven biomarkers correlated with viral RNA. Thirteen biomarkers were associated with a fatal outcome. No associations of biomarkers and hemorrhage or central nervous system disease were identified in this cohort. |
Rift valley fever viral load correlates with the human inflammatory response and coagulation pathway abnormalities in humans with hemorrhagic manifestations
de St Maurice A , Harmon J , Nyakarahuka L , Balinandi S , Tumusiime A , Kyondo J , Mulei S , Namutebi A , Knust B , Shoemaker T , Nichol ST , McElroy AK , Spiropoulou CF . PLoS Negl Trop Dis 2018 12 (5) e0006460 Rift Valley fever virus is an arbovirus that affects both livestock and humans throughout Africa and in the Middle East. Despite its endemicity throughout Africa, it is a rare event to identify an infected individual during the acute phase of the disease and an even rarer event to collect serial blood samples from the affected patient. Severely affected patients can present with hemorrhagic manifestations of disease. In this study we identified three Ugandan men with RVFV disease that was accompanied by hemorrhagic manifestations. Serial blood samples from these men were analyzed for a series of biomarkers specific for various aspects of human pathophysiology including inflammation, endothelial function and coagulopathy. There were significant differences between biomarker levels in controls and cases both early during the illness and after clearance of viremia. Positive correlation of viral load with markers of inflammation (IP-10, CRP, Eotaxin, MCP-2 and Granzyme B), markers of fibrinolysis (tPA and D-dimer), and markers of endothelial function (sICAM-1) were all noted. However, and perhaps most interesting given the fact that these individuals exhibited hemorrhagic manifestations of disease, was the finding of a negative correlation between viral load and P-selectin, ADAMTS13, and fibrinogen all of which are associated with coagulation pathways occurring on the endothelial surface. |
Statins suppress Ebola virus infectivity by interfering with glycoprotein processing
Shrivastava-Ranjan P , Flint M , Bergeron E , McElroy AK , Chatterjee P , Albarino CG , Nichol ST , Spiropoulou CF . mBio 2018 9 (3) Ebola virus (EBOV) infection is a major public health concern due to high fatality rates and limited effective treatments. Statins, widely used cholesterol-lowering drugs, have pleiotropic mechanisms of action and were suggested as potential adjunct therapy for Ebola virus disease (EVD) during the 2013-2016 outbreak in West Africa. Here, we evaluated the antiviral effects of statin (lovastatin) on EBOV infection in vitro Statin treatment decreased infectious EBOV production in primary human monocyte-derived macrophages and in the hepatic cell line Huh7. Statin treatment did not interfere with viral entry, but the viral particles released from treated cells showed reduced infectivity due to inhibition of viral glycoprotein processing, as evidenced by decreased ratios of the mature glycoprotein form to precursor form. Statin-induced inhibition of infectious virus production and glycoprotein processing was reversed by exogenous mevalonate, the rate-limiting product of the cholesterol biosynthesis pathway, but not by low-density lipoprotein. Finally, statin-treated cells produced EBOV particles devoid of the surface glycoproteins required for virus infectivity. Our findings demonstrate that statin treatment inhibits EBOV infection and suggest that the efficacy of statin treatment should be evaluated in appropriate animal models of EVD.IMPORTANCE Treatments targeting Ebola virus disease (EVD) are experimental, expensive, and scarce. Statins are inexpensive generic drugs that have been used for many years for the treatment of hypercholesterolemia and have a favorable safety profile. Here, we show the antiviral effects of statins on infectious Ebola virus (EBOV) production. Our study reveals a novel molecular mechanism in which statin regulates EBOV particle infectivity by preventing glycoprotein processing and incorporation into virus particles. Additionally, statins have anti-inflammatory and immunomodulatory effects. Since inflammation and dysregulation of the immune system are characteristic features of EVD, statins could be explored as part of EVD therapeutics. |
Whole blood-based multiplex immunoassays for the evaluation of human biomarker responses to emerging viruses in resource-limited regions
Harmon JR , Nichol ST , Spiropoulou CF , McElroy AK . Viral Immunol 2017 30 (9) 671-674 Many emerging viruses such as Ebola and Lassa occur in resource-limited areas of the world. The advent of multiplex immunoassays has facilitated the study of biomarkers of disease since only small amounts of clinical material are required; however, such assays are designed and validated for only plasma or serum. This is a significant impediment when studying infectious diseases in the context of an outbreak in a developing nation. Plasma or serum can be difficult to obtain in the field due to the need for additional processing of infectious materials. Evaluation of multiplex immunoassays using frozen and thawed human whole blood (WB) would permit additional analysis using a more readily available human clinical sample. In this study, frozen and thawed human WB was directly compared with frozen and thawed plasma from normal healthy donors in a series of multiplexed immunoassays for 59 different biomarkers. We demonstrate that most important biomarkers can be evaluated using thawed WB, which will facilitate the study of human cytokine and other biomarker responses to viruses emerging in resource-limited regions. |
A case of human Lassa virus infection with robust acute T-cell activation and long-term virus-specific T-cell responses
McElroy AK , Akondy RS , Harmon JR , Ellebedy AH , Cannon D , Klena JD , Sidney J , Sette A , Mehta AK , Kraft CS , Lyon MG , Varkey JB , Ribner BS , Nichol ST , Spiropoulou CF . J Infect Dis 2017 215 (12) 1862-1872 A nurse who acquired Lassa virus infection in Togo in the spring of 2016 was repatriated to the United States for care at Emory University Hospital. Serial sampling from this patient permitted the characterization of several aspects of the innate and cellular immune responses to Lassa virus. Although most of the immune responses correlated with the kinetics of viremia resolution, the CD8 T-cell response was of surprisingly high magnitude and prolonged duration, implying prolonged presentation of viral antigens. Indeed, long after viremia resolution, there was persistent viral RNA detected in the semen of the patient, accompanied by epididymitis, suggesting the male reproductive tract as 1 site of antigen persistence. Consistent with the magnitude of acute T-cell responses, the patient ultimately developed long-term, polyfunctional memory T-cell responses to Lassa virus. |
First newborn baby to receive experimental therapies survives Ebola virus disease
Dornemann J , Burzio C , Ronsse A , Sprecher A , De Clerck H , Van Herp M , Kolie MC , Yosifiva V , Caluwaerts S , McElroy AK , Antierens A . J Infect Dis 2017 215 (2) 171-174 A neonate born to an Ebola virus-positive woman was diagnosed with Ebola virus infection on her first day of life. The patient was treated with monoclonal antibodies (ZMapp), a buffy coat transfusion from an Ebola survivor, and the broad-spectrum antiviral GS-5734. On day 20, a venous blood specimen tested negative for Ebola virus by quantitative reverse-transcription polymerase chain reaction. The patient was discharged in good health on day 33 of life. Further follow-up consultations showed age-appropriate weight gain and neurodevelopment at the age of 12 months. This patient is the first neonate documented to have survived congenital infection with Ebola virus. |
Crimean-Congo hemorrhagic fever in humanized mice reveals glial cells as primary targets of neurological infection
Spengler JR , Keating MK , McElroy AK , Zivcec M , Coleman-McCray JD , Harmon JR , Bollweg BC , Goldsmith CS , Bergeron E , Keck JG , Zaki SR , Nichol ST , Spiropoulou CF . J Infect Dis 2017 216 (11) 1386-1397 Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne viral hemorrhagic disease seen exclusively in humans. Central nervous system (CNS) infection and neurological involvement have also been reported in CCHF. Here we inoculated NSGTM-SGM3 mice engrafted with human hematopoietic CD34+ stem cells with low passage CCHF virus strains isolated from human patients. Humanized mice develop lethal disease characterized by histopathological change in the liver and brain. To date, targets of neuroinfection and neuropathology have not been investigated in CCHF. CNS disease in humanized mice was characterized by gliosis, meningitis and meningoencephalitis, and glial cells were identified as principal targets of infection. Humanized mice represent a novel lethal model for studies of CCHF countermeasures, and CCHF-associated CNS disease. Our data suggests a role for astrocyte dysfunction in neurologic disease, and distinguish key regions of infection in the CNS for future investigations of CCHF. |
Defining antigen-specific plasmablast and memory B cell subsets in human blood after viral infection or vaccination
Ellebedy AH , Jackson KJ , Kissick HT , Nakaya HI , Davis CW , Roskin KM , McElroy AK , Oshansky CM , Elbein R , Thomas S , Lyon GM , Spiropoulou CF , Mehta AK , Thomas PG , Boyd SD , Ahmed R . Nat Immunol 2016 17 (10) 1226-34 Antigen-specific B cells bifurcate into antibody-secreting cells (ASCs) and memory B cells (MBCs) after infection or vaccination. ASCs (plasmablasts) have been extensively studied in humans, but less is known about B cells that become activated but do not differentiate into plasmablasts. Here we have defined the phenotype and transcriptional program of a subset of antigen-specific B cells, which we have called 'activated B cells' (ABCs), that were distinct from ASCs and were committed to the MBC lineage. We detected ABCs in humans after infection with Ebola virus or influenza virus and also after vaccination. By simultaneously analyzing antigen-specific ASCs and ABCs in human blood after vaccination against influenza virus, we investigated the clonal overlap and extent of somatic hypermutation (SHM) in the ASC (effector) and ABC (memory) lineages. Longitudinal tracking of vaccination-induced hemagglutinin (HA)-specific clones revealed no overall increase in SHM over time, which suggested that repeated annual immunization might have limitations in enhancing the quality of influenza-virus-specific antibody. |
Rift Valley fever virus: Unanswered questions
Bird BH , McElroy AK . Antiviral Res 2016 132 274-80 This mosquito-borne pathogen of humans and animals respects no international or geographic boundaries. It is currently found in parts of Africa, Madagascar, and the Arabian Peninsula where periodic outbreaks of severe and fatal disease occur, and threatens to spread into other geographic regions. In recent years, modern molecular techniques have led to many breakthroughs deepening our understanding of the mechanisms of RVFV virulence, phylogenetics, and the creation of several next-generation vaccine candidates. Despite tremendous progress in these areas, other challenges remain in RVF disease pathogenesis, the virus life-cycle, and outbreak response preparedness that deserve our attention. Here we discuss and highlight ten key knowledge gaps and challenges in RVFV research. Answers to these key questions may lead to the development of new effective therapeutics and enhanced control strategies for this serious human and veterinary health threat. |
Kinetic analysis of biomarkers in a cohort of US patients with Ebola virus disease
McElroy AK , Harmon JR , Flietstra TD , Campbell S , Mehta AK , Kraft CS , Lyon MG , Varkey JB , Ribner BS , Kratochvil CJ , Iwen PC , Smith PW , Ahmed R , Nichol ST , Spiropoulou CF . Clin Infect Dis 2016 63 (4) 460-7 BACKGROUND: Ebola virus (EBOV) infection causes a severe and often fatal disease. Despite the fact that more than 30 000 individuals have acquired Ebola virus disease (EVD), the medical and scientific community still does not have a clear understanding of the mechanisms by which EBOV causes such severe disease. METHODS: In this study, 54 biomarkers in plasma samples serially collected from 7 patients with EVD were analyzed in an attempt to define the kinetics of inflammatory modulators. Two clinical disease groups were defined (moderate and severe) based on the need for clinical support. Biomarkers were evaluated for correlation with viremia and clinical disease in an effort to identify pathways that could be useful targets of therapeutic intervention. RESULTS: Patients with severe disease had higher viremia than those with moderate disease. Several biomarkers of immune activation and control were significantly elevated in patients with moderate disease. A series of pro-inflammatory cytokines and chemokines were significantly elevated in patients with severe disease. CONCLUSIONS: Biomarkers that were associated with severe EVD were proinflammatory and indicative of endothelial or coagulation cascade dysfunction, as has been seen historically in patients with fatal outcomes. In contrast, biomarkers that were associated with moderate EVD were suggestive of a strong interferon response and control of both innate and adaptive responses. Therefore, clinical interventions that modulate the phenotype and magnitude of immune activation may be beneficial in treating EVD. |
Ebola virus persistence in semen of male survivors
Uyeki TM , Erickson BR , Brown S , McElroy AK , Cannon D , Gibbons A , Sealy T , Kainulainen MH , Schuh AJ , Kraft CS , Mehta AK , Lyon GM , Varkey JB , Ribner BS , Ellison RT 3rd , Carmody E , Nau GJ , Spiropoulou C , Nichol ST , Stroher U . Clin Infect Dis 2016 62 (12) 1552-1555 We investigated the duration of Ebola virus (EBOV) ribonucleic acid (RNA) and infectious EBOV in semen specimens of five Ebola virus disease (EVD) survivors. EBOV RNA and infectious EBOV was detected by real-time RT-PCR and virus culture out to 290 days and 70 days, respectively after EVD onset. |
Reply to Fedson
McElroy AK , Spiropoulou CF . J Infect Dis 2015 211 (4) 662-3 We appreciate the interest in our recent article [1] on biomarkers in Ebola virus disease (EVD) and the editorial comments provided by Fedson. In his editorial, Fedson points out that the evidence of endothelial dysfunction that we reported in patients affected by EVD is also commonly observed in other forms of sepsis. He brings attention to a mouse study that indicated that selective inhibition of nuclear factor κB signaling in endothelial cells in the context of bacterial sepsis provided protection from disease [2], suggesting that downregulation of the local inflammatory response at the endothelial cell level could be protective to patients. Additionally, he comments on a small clinical trial of statins in patients with sepsis; this study showed decreased progression to severe sepsis in statin-treated patients [3]. This result is attributed to the role of statins in stabilizing the endothelium and in its local antiinflammatory effects on endothelial cells. Finally, Fedson suggests the use of statins as adjunctive therapy in managing patients who have EVD. | | We agree that statins should be considered as adjunctive therapy for EVD. In fact, we suggested the use of statins in patients with EVD in a subsequent study, in which we examined the differences in biomarkers and clinical outcomes between adult and pediatric patients with EVD [4]. In that study, we observed direct evidence of endothelial dysfunction, demonstrated by elevated levels of soluble intercellular adhesion molecule and soluble vascular cell adhesion molecule in pediatric patients who had fatal outcomes, and normal levels of these factors in pediatric patients who survived infection. |
Relationship Between Ebola Virus Real-Time Quantitative Polymerase Chain Reaction-Based Threshold Cycle Value and Virus Isolation From Human Plasma.
Spengler JR , McElroy AK , Harmon JR , Stroher U , Nichol ST , Spiropoulou CF . J Infect Dis 2015 212 Suppl 2 S346-9 We performed a longitudinal analysis of plasma samples obtained from 4 patients with Ebola virus (EBOV) disease (EVD) to determine the relationship between the real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR)-based threshold cycle (Ct) value and the presence of infectious EBOV. EBOV was not isolated from plasma samples with a Ct value of >35.5 or >12 days after onset of symptoms. EBOV was not isolated from plasma samples in which anti-EBOV nucleoprotein immunoglobulin G was detected. These data demonstrate the utility of interpreting qRT-PCR results in the context of the course of EBOV infection and associated serological responses for patient-management decisions. |
The use of TKM-100802 and convalescent plasma in 2 patients with Ebola virus disease in the United States
Kraft CS , Hewlett AL , Koepsell S , Winkler AM , Kratochvil CJ , Larson L , Varkey JB , Mehta AK , Lyon GM 3rd , Friedman-Moraco RJ , Marconi VC , Hill CE , Sullivan JN , Johnson DW , Lisco SJ , Mulligan MJ , Uyeki TM , McElroy AK , Sealy T , Campbell S , Spiropoulou C , Stroher U , Crozier I , Sacra R , Connor MJ Jr , Sueblivong V , Franch HA , Smith PW , Ribner BS . Clin Infect Dis 2015 61 (4) 496-502 The current West Africa Ebola virus disease (EVD) outbreak has resulted in multiple individuals being medically evacuated to other countries for clinical management. We report two patients who were transported from West Africa to the United States for treatment of EVD. Both patients received aggressive supportive care measures, as well as an investigational therapeutic (TKM-100802) and convalescent plasma. While one patient experienced critical illness with multi-organ failure requiring mechanical ventilation and renal replacement therapy, both patients recovered without serious long-term sequelae to date. It is unclear what role the experimental drug and convalescent plasma had in the recovery of these patients. Prospective clinical trials are needed to delineate the role of investigational therapies in the care of patients with EVD. |
Human Ebola virus infection results in substantial immune activation
McElroy AK , Akondy RS , Davis CW , Ellebedy AH , Mehta AK , Kraft CS , Lyon GM , Ribner BS , Varkey J , Sidney J , Sette A , Campbell S , Stroher U , Damon I , Nichol ST , Spiropoulou CF , Ahmed R . Proc Natl Acad Sci U S A 2015 112 (15) 4719-24 Four Ebola patients received care at Emory University Hospital, presenting a unique opportunity to examine the cellular immune responses during acute Ebola virus infection. We found striking activation of both B and T cells in all four patients. Plasmablast frequencies were 10-50% of B cells, compared with less than 1% in healthy individuals. Many of these proliferating plasmablasts were IgG-positive, and this finding coincided with the presence of Ebola virus-specific IgG in the serum. Activated CD4 T cells ranged from 5 to 30%, compared with 1-2% in healthy controls. The most pronounced responses were seen in CD8 T cells, with over 50% of the CD8 T cells expressing markers of activation and proliferation. Taken together, these results suggest that all four patients developed robust immune responses during the acute phase of Ebola virus infection, a finding that would not have been predicted based on our current assumptions about the highly immunosuppressive nature of Ebola virus. Also, quite surprisingly, we found sustained immune activation after the virus was cleared from the plasma, observed most strikingly in the persistence of activated CD8 T cells, even 1 mo after the patients' discharge from the hospital. These results suggest continued antigen stimulation after resolution of the disease. From these convalescent time points, we identified CD4 and CD8 T-cell responses to several Ebola virus proteins, most notably the viral nucleoprotein. Knowledge of the viral proteins targeted by T cells during natural infection should be useful in designing vaccines against Ebola virus. |
Biomarkers for understanding Ebola virus disease
McElroy AK , Spiropoulou CF . Biomark Med 2014 8 (9) 1053-6 The Filoviridae family of negative-strand RNA viruses is feared for these viruses’ ability to cause hemorrhage and death in infected individuals. Depending on the infecting species of virus, the case fatality rate can be anywhere from 30 to 90% [1]. Ebola virus (EBOV), Sudan virus (SUDV) and Bundibugyo virus (BDBV) are the three clinically significant species that cause Ebola virus disease (EVD). These viruses are typically found in sub-Saharan Africa, and cause sporadic outbreaks that can be brought under control with appropriate rapid public health responses. However, the recent emergence of EBOV in west Africa in early 2014 [2] has been challenging to contain, and has spread to three countries in the region so far. This outbreak, now the largest EBOV outbreak on record, is still ongoing at the time of writing this editorial. | Efforts by many investigators have led to the development of potential vaccines and therapeutics [3,4]. However, none of these have yet resulted in commercially available products, and are unlikely to do so in the near future due to the cost of developing novel products for human use and the challenges of conducting a clinical trial during an outbreak in a developing nation that lacks the necessary healthcare infrastructure. The most cost-effective and timely option would be to identify an already approved drug that might be effective at combating disease caused by EBOV and SUDV for off-label use by treating physicians. In order to identify currently licensed drugs that might be beneficial, we need to know more about the pathophysiology of the disease. Biomarker analyses could prove to be useful for this purpose. |
Clinical care of two patients with Ebola virus disease in the United States
Lyon GM , Mehta AK , Varkey JB , Brantly K , Plyler L , McElroy AK , Kraft CS , Towner JS , Spiropoulou C , Stroher U , Uyeki TM , Ribner BS . N Engl J Med 2014 371 (25) 2402-9 West Africa is currently experiencing the largest outbreak of Ebola virus disease (EVD) in history. Two patients with EVD were transferred from Liberia to our hospital in the United States for ongoing care. Malaria had also been diagnosed in one patient, who was treated for it early in the course of EVD. The two patients had substantial intravascular volume depletion and marked electrolyte abnormalities. We undertook aggressive supportive measures of hydration (typically, 3 to 5 liters of intravenous fluids per day early in the course of care) and electrolyte correction. As the patients' condition improved clinically, there was a concomitant decline in the amount of virus detected in plasma. |
Von Willebrand factor is elevated in individuals infected with Sudan virus and is associated with adverse clinical outcomes
McElroy AK , Erickson BR , Flietstra TD , Rollin PE , Towner JS , Nichol ST , Spiropoulou CF . Viral Immunol 2014 28 (1) 71-3 Sudan virus (SUDV) is a member of the Filoviridae family that has been associated with sporadic outbreaks of human disease in sub-Saharan Africa. The filoviruses are notable for the high frequencies with which they cause both hemorrhagic manifestations and death in infected individuals. Recently, we reported an extensive biomarker analysis of patient specimens from the Gulu SUDV outbreak. In that study, we found evidence of endothelial dysfunction and alterations of factors important to the coagulation pathways. The complex intersection between the endothelium, coagulation, and immunity is further explored in this study where we examine several additional biomarkers using the same patient specimens. We report that von Willebrand factor (vWF), a protein that promotes platelet adhesion to the injured endothelium, is elevated in SUDV-infected individuals compared to normally reported values in healthy individuals. Furthermore, vWF is associated with a fatal outcome in SUDV-infected pediatric patients. In addition, we find that vWF is elevated in individuals who have hemorrhagic manifestations of disease, suggesting excessive thrombosis in these patients. |
Biomarker correlates of survival in pediatric patients with Ebola virus disease
McElroy AK , Erickson BR , Flietstra TD , Rollin PE , Nichol ST , Towner JS , Spiropoulou CF . Emerg Infect Dis 2014 20 (10) 1683-90 Outbreaks of Ebola virus disease (EVD) occur sporadically in Africa and are associated with high case-fatality rates. Historically, children have been less affected than adults. The 2000-2001 Sudan virus-associated EVD outbreak in the Gulu district of Uganda resulted in 55 pediatric and 161 adult laboratory-confirmed cases. We used a series of multiplex assays to measure the concentrations of 55 serum analytes in specimens from patients from that outbreak to identify biomarkers specific to pediatric disease. Pediatric patients who survived had higher levels of the chemokine regulated on activation, normal T-cell expressed and secreted marker and lower levels of plasminogen activator inhibitor 1, soluble intracellular adhesion molecule, and soluble vascular cell adhesion molecule than did pediatric patients who died. Adult patients had similar levels of these analytes regardless of outcome. Our findings suggest that children with EVD may benefit from different treatment regimens than those for adults. |
Rift Valley fever virus encephalitis is associated with an ineffective systemic immune response and activated T cell infiltration into the CNS in an immunocompetent mouse model
Dodd KA , McElroy AK , Jones TL , Zaki SR , Nichol ST , Spiropoulou CF . PLoS Negl Trop Dis 2014 8 (6) e2874 BACKGROUND: Rift Valley fever virus (RVFV) causes outbreaks of severe disease in livestock and humans throughout Africa and the Arabian Peninsula. In people, RVFV generally causes a self-limiting febrile illness but in a subset of individuals, it progresses to more serious disease. One manifestation is a delayed-onset encephalitis that can be fatal or leave the afflicted with long-term neurologic sequelae. In order to design targeted interventions, the basic pathogenesis of RVFV encephalitis must be better understood. METHODOLOGY/PRINCIPAL FINDINGS: To characterize the host immune responses and viral kinetics associated with fatal and nonfatal infections, mice were infected with an attenuated RVFV lacking NSs (DeltaNSs) that causes lethal disease only when administered intranasally (IN). Following IN infection, C57BL/6 mice developed severe neurologic disease and succumbed 7-9 days post-infection. In contrast, inoculation of DeltaNSs virus subcutaneously in the footpad (FP) resulted in a subclinical infection characterized by a robust immune response with rapid antibody production and strong T cell responses. IN-inoculated mice had delayed antibody responses and failed to clear virus from the periphery. Severe neurological signs and obtundation characterized end stage-disease in IN-inoculated mice, and within the CNS, the development of peak virus RNA loads coincided with strong proinflammatory responses and infiltration of activated T cells. Interestingly, depletion of T cells did not significantly alter survival, suggesting that neurologic disease is not a by-product of an aberrant immune response. CONCLUSIONS/SIGNIFICANCE: Comparison of fatal (IN-inoculated) and nonfatal (FP-inoculated) DeltaNSs RVFV infections in the mouse model highlighted the role of the host immune response in controlling viral replication and therefore determining clinical outcome. There was no evidence to suggest that neurologic disease is immune-mediated in RVFV infection. These results provide important insights for the future design of vaccines and therapeutic options. |
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