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Duvvuri V.R.,York Institute of Health Research | Duvvuri B.,York Institute of Health Research | Alice C.,York Institute of Health Research | Wu G.E.,York University | And 6 more authors.
PLoS ONE | Year: 2014

In 2013, a novel avian influenza H7N9 virus was identified in human in China. The antigenically distinct H7N9 surface glycoproteins raised concerns about lack of cross-protective neutralizing antibodies. Epitope-specific preexisting T-cell immunity was one of the protective mechanisms in pandemic 2009 H1N1 even in the absence of cross-protective antibodies. Hence, the assessment of preexisting CD4+ T-cell immunity to conserved epitopes shared between H7N9 and human influenza A viruses (IAV) is critical. A comparative whole proteome-wide immunoinformatics analysis was performed to predict the CD4+ T-cell epitopes that are commonly conserved within the proteome of H7N9 in reference to IAV subtypes (H1N1, H2N2, and H3N2). The CD4+ T-cell epitopes that are commonly conserved (∼556) were further screened against the Immune Epitope Database (IEDB) to validate their immunogenic potential. This analysis revealed that 45.5% (253 of 556) epitopes are experimentally proven to induce CD4+ T-cell memory responses. In addition, we also found that 23.3% of CD4+ T-cell epitopes have ≥90% of sequence homology with experimentally defined CD8+ T-cell epitopes. We also conducted the population coverage analysis across different ethnicities using commonly conserved CD4+ T-cell epitopes and corresponding HLA-DRB1 alleles. Interestingly, the indigenous populations from Canada, United States, Mexico and Australia exhibited low coverage (28.65% to 45.62%) when compared with other ethnicities (57.77% to 94.84%). In summary, the present analysis demonstrate an evidence on the likely presence of preexisting T-cell immunity in human population and also shed light to understand the potential risk of H7N9 virus among indigenous populations, given their high susceptibility during previous pandemic influenza events. This information is crucial for public health policy, in targeting priority groups for immunization programs. © 2014 Duvvuri et al.


Lou Y.,Hong Kong Polytechnic University | Wu J.,York Institute of Health Research | Wu J.,York University
Ecological Complexity | Year: 2014

In vector-borne disease modeling, a key assumption is the host-vector interaction pattern encapsulated in the host seeking rate. Here, a model for Lyme disease dynamics with different host seeking rates is used to investigate how different patterns of tick-host interaction affect the model predictions in the context of tick-borne disease control. Three different host seeking behaviors (the frequency-dependent rate, the density-dependent rate and the Holling type 2 rate) are compared. The comparison of results illustrates not only variable relationships between rodents and tick abundance but also different implications for disease control: (i) for the model with the frequency-dependent rate, reducing rodents is always bad for containing the disease; (ii) for density-dependent or the Holling type 2 rate, reducing or increasing rodent population should be carefully considered, since large host population may facilitate the development of immature ticks, resulting in the immature tick population level so low to sustain the transmission cycle. Furthermore, we distinguish different mechanisms of dilution effects (pathogen reduction with the increasing of the host biodiversity) from different tick-host interaction patterns. © 2013 Elsevier B.V.


Wu X.,York Institute of Health Research | Wu X.,York University | Duvvuri V.R.,York Institute of Health Research | Lou Y.,Hong Kong Polytechnic University | And 4 more authors.
Journal of Theoretical Biology | Year: 2013

A mechanistic model of the tick vector of Lyme disease, Ixodes scapularis, was adapted to a deterministic structure. Using temperature normals smoothed by Fourier analysis to generate seasonal temperature-driven development rates and host biting rates, and a next generation matrix approach, the model was used to obtain values for the basic reproduction number (. R0) for I. scapularis at locations in southern Canada where the tick is established and emerging. The R0 at Long Point, Point Pelee and Chatham sites where I. scapularis are established, was estimated at 1.5, 3.19 and 3.65, respectively. The threshold temperature conditions for tick population survival (. R0=1) were shown to be the same as those identified using the mechanistic model (2800-3100 cumulative annual degree days >0 ° C), and a map of R0 for I. scapularis, the first such map for an arthropod vector, was drawn for Canada east of the Rocky Mountains. This map supports current risk assessments for Lyme disease risk emergence in Canada. Sensitivity analysis identified host abundance, tick development rates and summer temperatures as highly influential variables in the model, which is consistent with our current knowledge of the biology of this tick. The development of a deterministic model for I. scapularis that is capable of providing values for R0 is a key step in our evolving ability to develop tools for assessment of Lyme disease risk emergence and for development of public health policies on surveillance, prevention and control. © 2012 Elsevier Ltd.


Duvvuri V.R.,York University | Duvvuri V.R.,York Institute of Health Research | Duvvuri B.,York University | Jamnik V.,York University | And 6 more authors.
BMC Infectious Diseases | Year: 2013

Background: The 2009 pandemic influenza was milder than expected. Based on the apparent lack of pre-existing cross-protective antibodies to the A (H1N1)pdm09 strain, it was hypothesized that pre-existing CD4+ T cellular immunity provided the crucial immunity that led to an attenuation of disease severity. We carried out a pilot scale study by conducting in silico and in vitro T cellular assays in healthy population, to evaluate the pre-existing immunity to A (H1N1)pdm09 strain.Methods: Large-scale epitope prediction analysis was done by examining the NCBI available (H1N1) HA proteins. NetMHCIIpan, an eptiope prediction tool was used to identify the putative and shared CD4+ T cell epitopes between seasonal H1N1 and A (H1N1)pdm09 strains. To identify the immunogenicity of these putative epitopes, human IFN-γ-ELISPOT assays were conducted using the peripheral blood mononuclear cells from fourteen healthy human donors. All donors were screened for the HLA-DRB1 alleles.Results: Epitope-specific CD4+ T cellular memory responses (IFN-γ) were generated to highly conserved HA epitopes from majority of the donors (93%). Higher magnitude of the CD4+ T cell responses was observed in the older adults. The study identified two HA2 immunodominant CD4+ T cell epitopes, of which one was found to be novel.Conclusions: The current study provides a compelling evidence of HA epitope specific CD4+ T cellular memory towards A (H1N1)pdm09 strain. These well-characterized epitopes could recruit alternative immunological pathways to overcome the challenge of annual seasonal flu vaccine escape. © 2013 Duvvuri et al.; licensee BioMed Central Ltd.


Duvvuri B.,York University | Duvvuri V.R.S.K.,York University | Duvvuri V.R.S.K.,York Institute of Health Research | Grigull J.,York University | And 4 more authors.
Immunogenetics | Year: 2011

Pathogenic common variable immunodeficiency diseases (CVID) are genetic, usually inherited diseases for which a limited number of genetic defects have been implicated. As CVID presents with a wide range of clinical characteristics, there are likely diverse and for the most part unidentified genetic causes. In some individuals, defects in somatic hypermutation (SHM) have been suggested as the underlying cause of CVID. To address the mechanisms of SHM defects in CVID, we conducted a comprehensive mutational analysis of immunoglobulin heavy chain sequences from CVID patients. We identified several remarkably specific alterations in the spectra of SHM in comparison to healthy individuals. We provide evidence that some CVID cases are associated with defective repair of AID-induced mutations by the DNA mismatch repair (MMR) machinery. Our findings together with reports of increased chromosomal radiosensitivity AR and associated lymphoproliferative disorders amongst CVID patients, suggest that altered DNA damage repair may be a cause of CVID. © 2010 Springer-Verlag.


Duvvuri V.R.S.K.,York Institute of Health Research | Duvvuri V.R.S.K.,York University | Duvvuri V.R.S.K.,University of Toronto | Moghadas S.M.,National Research Council Canada | And 10 more authors.
Influenza and other Respiratory Viruses | Year: 2010

Background: The relatively mild nature of the 2009 influenza pandemic (nH1N1) highlights the overriding importance of pre-existing immune memory. The absence of cross-reactive antibodies to nH1N1 in most individuals suggests that such attenuation may be attributed to pre-existing cellular immune responses to epitopes shared between nH1N1 virus and previously circulating strains of inter-pandemic influenza A viruses. Results: We sought to identify potential CD4+ T cell epitopes and predict the level of cross-reactivity of responding T cells. By performing large-scale major histocompatibility complex II analyses on Hemagglutinin (HA) proteins, we investigated the degree of T-cell cross-reactivity between seasonal influenza A (sH1N1, H3N2) from 1968 to 2009 and nH1N1 strains. Each epitope was examined against all the protein sequences that correspond to sH1N1, H3N2, and nH1N1. T-cell cross-reactivity was estimated to be 52%, and maximum conservancy was found between sH1N1 and nH1N1 with a significant correlation (P < 0·05). Conclusions: Given the importance of cellular responses in kinetics of influenza infection in humans, our findings underscore the role of T-cell assays for understanding the inter-pandemic variability in severity and for planning treatment methods for emerging influenza viruses. © 2010 Blackwell Publishing Ltd.


Ogden N.H.,Public Health Agency of Canada | Radojevic M.,Public Health Agency of Canada | Wu X.,York Institute of Health Research | Wu X.,York University | And 4 more authors.
Environmental Health Perspectives | Year: 2014

Background: The extent to which climate change may affect human health by increasing risk from vector-borne diseases has been under considerable debate. Objectives: We quantified potential effects of future climate change on the basic reproduction number (R0) of the tick vector of Lyme disease, Ixodes scapularis, and explored their importance for Lyme disease risk, and for vector-borne diseases in general. Methods: We applied observed temperature data for North America and projected temperatures using regional climate models to drive an I. scapularis population model to hindcast recent, and project future, effects of climate warming on R0. Modeled R0 increases were compared with R0 ranges for pathogens and parasites associated with variations in key ecological and epidemiological factors (obtained by literature review) to assess their epidemiological importance. Results: R0 for I. scapularis in North America increased during the years 1971-2010 in spatiotemporal patterns consistent with observations. Increased temperatures due to projected climate change increased R0 by factors (2-5 times in Canada and 1.5-2 times in the United States), comparable to observed ranges of R0 for pathogens and parasites due to variations in strains, geographic locations, epidemics, host and vector densities, and control efforts. Conclusions: Climate warming may have co-driven the emergence of Lyme disease in northeastern North America, and in the future may drive substantial disease spread into new geographic regions and increase tick-borne disease risk where climate is currently suitable. Our findings highlight the potential for climate change to have profound effects on vectors and vector-borne diseases, and the need to refocus efforts to understand these effects.


PubMed | York Institute of Health Research
Type: Journal Article | Journal: Influenza and other respiratory viruses | Year: 2010

The relatively mild nature of the 2009 influenza pandemic (nH1N1) highlights the overriding importance of pre-existing immune memory. The absence of cross-reactive antibodies to nH1N1 in most individuals suggests that such attenuation may be attributed to pre-existing cellular immune responses to epitopes shared between nH1N1 virus and previously circulating strains of inter-pandemic influenza A viruses.We sought to identify potential CD4+ T cell epitopes and predict the level of cross-reactivity of responding T cells. By performing large-scale major histocompatibility complex II analyses on Hemagglutinin (HA) proteins, we investigated the degree of T-cell cross-reactivity between seasonal influenza A (sH1N1, H3N2) from 1968 to 2009 and nH1N1 strains. Each epitope was examined against all the protein sequences that correspond to sH1N1, H3N2, and nH1N1. T-cell cross-reactivity was estimated to be 52%, and maximum conservancy was found between sH1N1 and nH1N1 with a significant correlation (P < 0.05).Given the importance of cellular responses in kinetics of influenza infection in humans, our findings underscore the role of T-cell assays for understanding the inter-pandemic variability in severity and for planning treatment methods for emerging influenza viruses.

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