Last data update: May 13, 2024. (Total: 46773 publications since 2009)
Records 1-7 (of 7 Records) |
Query Trace: Moore ML[original query] |
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A respiratory syncytial virus attachment (G) gene variant associated with more severe disease in infants decreases fusion (F) protein expression which may facilitate immune evasion.
Human S , Hotard AL , Rostad CA , Lee S , McCormick L , Larkin EK , Peret TCT , Jorba J , Lanzone J , Gebretsadik T , Williams JV , Bloodworth M , Stier M , Carroll K , Peebles RS Jr , Anderson LJ , Hartert TV , Moore ML . J Virol 2020 95 (2) This study identified a genotype of RSV associated with increased acute respiratory disease severity in a cohort of term, previously healthy infants. The genotype (2stop+A4G) consists of two components. The A4G component is a prevalent point mutation in the 4(th) position of the gene end transcription termination signal of the G gene of currently circulating RSV strains. The 2stop component is two tandem stop codons at the G gene terminus, preceding the gene end transcription termination signal. To investigate the biological role of these RSV G gene mutations, recombinant RSV strains harboring either a wild type A2 strain G gene (one stop codon preceding a wild type gene end signal), an A4G gene end signal preceded by one stop codon, or the 2stop+A4G virulence-associated combination were generated and characterized. Infection with the rA4G RSV mutant resulted in transcriptional read-through and lower G and fusion (F) protein levels relative to wild type. Addition of a second stop codon preceding the A4G point mutation (2stop+A4G) restored G protein expression but retained lower F protein levels. These data suggest that RSV G and F glycoprotein expression is regulated by transcriptional and translational read-through. Notably, while rA4G and r2stop+A4G RSV were attenuated in cells and in naïve BALB/c mice compared to wild type RSV, the r2stop+A4G RSV was better able to infect BALB/c mice in the presence of pre-existing immunity in comparison to rA4G RSV. Together these factors may contribute to the maintenance and virulence of the 2stop+A4G genotype in currently circulating RSV-A strains.IMPORTANCE Strain-specific differences in respiratory syncytial virus (RSV) isolates are associated with differential pathogenesis in mice. However, the role of RSV genotypes in human infection is incompletely understood. This work demonstrates that one such genotype, 2stop+A4G, present in the RSV attachment (G) gene terminus is associated with greater infant disease severity. The genotype consists of two tandem stop codons preceding an A-to-G point mutation in the 4(th) position of the G gene end transcription termination signal. Virologically, the 2stop+A4G RSV genotype results in reduced levels of the RSV fusion (F) glycoprotein. A recombinant 2stop+A4G RSV was better able to establish infection in the presence of existing RSV immunity compared to a virus harboring the common A4G mutation. These data suggest that regulation of G and F expression has implications for virulence and potentially immune evasion. |
Mutating the CX3C motif in the G protein should make a live respiratory syncytial virus vaccine safer and more effective.
Boyoglu-Barnum S , Todd SO , Meng J , Barnum TR , Chirkova T , Haynes LM , Jadhao SJ , Tripp RA , Oomens AG , Moore ML , Anderson LJ . J Virol 2017 91 (10) Respiratory syncytial virus (RSV) belongs to the family Paramyxoviridae and is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. Through a CX3C chemokine motif (182CWAIC186) in the G protein, RSV binds to the corresponding chemokine receptor, CX3CR1. Since RSV binding to CX3CR1 contributes to disease pathogenesis, we investigated whether a mutation in the CX3C motif by insertion of an alanine A186 within the CX3C motif to CX4C (182CWAIAC187), known to block binding to CX3CR1, might decrease disease. We studied the effect of the CX4C mutation in two strains of RSV (A2 and r19F) in a mouse challenge model. We included the RSV r19F because it induces mucous production and airway resistance, two manifestations of RSV infection in humans, in mice. Compared to wildtype virus (wt), mice infected with the CX4C had a 0.7 to 1.2 log10-fold lower virus titer in the lung at 5 days p.i. and had markedly reduced weight loss, pulmonary inflammatory cell infiltration, mucous production, and airway resistance after challenge. This decrease in disease was not dependent on decrease in virus replication but did correspond to a decrease in pulmonary Th2 and inflammatory cytokines. Mice infected with CX4C viruses also had higher antibody titers and a Th1 biased T cell memory response at 75 days pi. These results suggest that the CX4C mutation in the G protein could improve the safety and efficacy of a live attenuated RSV vaccine.Importance RSV binds to the corresponding chemokine receptor, CX3CR1, through a CX3C chemokine motif (182CWAIC186) in the G protein. RSV binding to CX3CR1 contributes to disease pathogenesis, therefore, we investigated whether a mutation in the CX3C motif by insertion of an alanine A186 within the CX3C motif to CX4C (182CWAIAC187), known to block binding to CX3CR1, might decrease disease. The effect of this mutation and treatment with the F(ab')2 form of the anti-RSV G 131-2G mAb show that mutating the CX3C motif to CX4C blocks much of the disease and immune modulation associated with the G protein and should improve the safety and efficacy of a live attenuated RSV vaccine. |
A polyvalent inactivated rhinovirus vaccine is broadly immunogenic in rhesus macaques
Lee S , Nguyen MT , Currier MG , Jenkins JB , Strobert EA , Kajon AE , Madan-Lala R , Bochkov YA , Gern JE , Roy K , Lu X , Erdman DD , Spearman P , Moore ML . Nat Commun 2016 7 12838 As the predominant aetiological agent of the common cold, human rhinovirus (HRV) is the leading cause of human infectious disease. Early studies showed that a monovalent formalin-inactivated HRV vaccine can be protective, and virus-neutralizing antibodies (nAb) correlated with protection. However, co-circulation of many HRV types discouraged further vaccine efforts. Here, we test the hypothesis that increasing virus input titres in polyvalent inactivated HRV vaccine may result in broad nAb responses. We show that serum nAb against many rhinovirus types can be induced by polyvalent, inactivated HRVs plus alhydrogel (alum) adjuvant. Using formulations up to 25-valent in mice and 50-valent in rhesus macaques, HRV vaccine immunogenicity was related to sufficient quantity of input antigens, and valency was not a major factor for potency or breadth of the response. Thus, we have generated a vaccine capable of inducing nAb responses to numerous and diverse HRV types. |
An anti-G protein monoclonal antibody treats RSV disease more effectively than an anti-F monoclonal antibody in BALB/c mice
Boyoglu-Barnum S , Todd SO , Chirkova T , Barnum TR , Gaston KA , Haynes LM , Tripp RA , Moore ML , Anderson LJ . Virology 2015 483 117-125 Respiratory syncytial virus (RSV) belongs to the family Paramyxoviridae and is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. To clarify the potential for an anti-G mAb, 131-2G which has both anti-viral and anti-inflammatory effects, to effectively treat RSV disease, we determined the kinetics of its effect compared to the effect of the anti-F mAb, 143-6C on disease in mice. Treatment administered three days after RSV rA2-line19F (r19F) infection showed 131-2G decreased breathing effort, pulmonary mucin levels, weight loss, and pulmonary inflammation earlier and more effectively than treatment with mAb 143-6C. Both mAbs stopped lung virus replication at day 5 post-infection. These data show that, in mice, anti-G protein mAb is superior to treating disease during RSV infection than an anti-F protein mAb similar to Palivizumab. This combination of anti-viral and anti-inflammatory activity makes 131-2G a promising candidate for treating for active human RSV infection. |
Prophylaxis with a respiratory syncytial virus (RSV) anti-G protein monoclonal antibody shifts the adaptive immune response to RSV rA2-line19F infection from Th2 to Th1 in BALB/c mice
Boyoglu-Barnum S , Chirkova T , Todd SO , Barnum TR , Gaston KA , Jorquera P , Haynes LM , Tripp RA , Moore ML , Anderson LJ . J Virol 2014 88 (18) 10569-83 Respiratory syncytial virus (RSV) is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. In the present study, we investigated the effect of prophylactic treatment with the intact and F(ab')2 forms of an anti-G protein monoclonal antibody (mAb), 131-2G, on the humoral and cellular adaptive immune response to RSV rA2-line19F (r19F) challenge in BALB/c mice. The F(ab')2 form of 131-2G does not decrease virus replication but intact 131-2G does. The serum specimens for antibodies and spleen cells for memory T cell responses to RSV antigens were analyzed at 30, 45, 75 and 95 p.i. with/without prior treatment with 131-2G. The ratios of Th2/Th1 antibody isotypes at each time p.i indicated that both forms of mAb 131-2G shifted the subclass response from a Th2 (IgG1 and IgG2b) to a Th1 (IgG2A) bias. The ratio of IgG1/IgG2A antibody titer was 3-fold to 10-fold higher for untreated than mAb treated mice. There was also some increase in IgG (22%+/-13 increase) and neutralization (32% increase) in antibodies with mAb 131-2G prophylaxis at 75 days p.i. Treatment with 131-2G significantly (p≤0.001) decreased the percent of IL-4 positive CD4 and CD8 in RSV stimulated spleen cells at all times p.i. while percent of IFN-gamma T cells significantly (p≤0.001) increased ≥75 days p.i. The shift from a Th2 to a Th1 biased T cell response in treated compared to untreated mice likely was directed by the much higher levels of T-box transcription factor (Tbet) (≥45% vs <10%) in CD4 and CD8 T cells and lower levels of Gata-3 (≤2% vs ≥6%) in CD4 T cells in peptide stimulated, day 75 p.i. spleen cells. These data show that the RSV G protein affects both humoral and cellular adaptive immune responses and induction of 131-2G-like antibodies might improve the safety and long term efficacy of an RSV vaccine. IMPORTANCE: The data in this report suggest that the RSV G protein not only contributes to disease but also dampens the host immune response to infection. Both effects of G likely contribute to difficulties in achieving an effective vaccine. The ability of mAb 131-2G to block these effects of G suggests that inducing antibodies similar to 131-2G should prevent disease and enhance the adaptive immune response with later RSV infection. The fact that 131-2G binds to the 13 aa region conserved among all strains and flanking sequences are conserved within Group A or within Group B strains, simplifies the task of developing a vaccine to induce 131-2G-like antibodies. If our findings in mice apply to humans, then including the 131-2G binding region of G in a vaccine should improve its safety and efficacy. |
A respiratory syncytial virus (RSV) anti-G protein F(ab')2 monoclonal antibody suppresses mucous production and breathing effort in RSV rA2-line19F-infected BALB/c mice
Boyoglu-Barnum S , Gaston KA , Todd SO , Boyoglu C , Chirkova T , Barnum TR , Jorquera P , Haynes LM , Tripp RA , Moore ML , Anderson LJ . J Virol 2013 87 (20) 10955-67 Respiratory syncytial virus (RSV) belongs to the family Paramyxoviridae and is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. Increased airway resistance and increased airway mucin production are two manifestations of RSV infection in children. RSV rA2-line19F infection induces pulmonary mucous production and increased breathing effort in BALB/c mice and provides a way to assess these manifestations of RSV disease in an animal model. In the present study, we investigated the effect of prophylactic treatment with the F(ab')2 form of the anti-G protein monoclonal antibody (MAb) 131-2G on disease in RSV rA2-line19F-challenged mice. F(ab')2 131-2G does not affect virus replication. It and the intact form that does decrease virus replication prevented increased breathing effort and airway mucin production, as well as weight loss, pulmonary inflammatory-cell infiltration, and the pulmonary substance P and pulmonary Th2 cytokine levels that occur in mice challenged with this virus. These data suggest that the RSV G protein contributes to prominent manifestations of RSV disease and that MAb 131-2G can prevent these manifestations of RSV disease without inhibiting virus infection. |
Trends in mortality of tuberculosis patients in the United States: the long-term perspective
Barnes RF , Moore ML , Garfein RS , Brodine S , Strathdee SA , Rodwell TC . Ann Epidemiol 2011 21 (10) 791-5 PURPOSE: To describe long-term trends in tuberculosis (TB) mortality and to compare trends estimated from two different sources of public health surveillance data. METHODS: Trends and changes in trend were estimated by joinpoint regression. Comparisons between data sets were made by fitting a Poisson regression model. RESULTS: Since 1900, TB mortality rates estimated from death certificates have declined steeply, except for a period of no change in the 1980s. This decade had long-term consequences resulting in more TB deaths in later years than would have occurred had there been no flattening of the trend. Recent trends in TB mortality estimated from National Tuberculosis Surveillance System (NTSS) data, which record all-cause mortality, differed from trends based on death certificates. In particular, NTSS data showed TB mortality rates flattening since 2002. CONCLUSIONS: Estimates of trends in TB mortality vary by data source, and therefore interpretation of the success of control efforts will depend on the surveillance data set used. The data sets may be subject to different biases that vary with time. One data set showed a sustained improvement in the control of TB since the early 1990s whereas the other indicated that the rate of TB mortality was no longer declining. |
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