Recipient Organization
OREGON STATE UNIVERSITY
(N/A)
CORVALLIS,OR 97331
Performing Department
Biomedical Sciences
Non Technical Summary
Infectious disease emergence is a clear and imminent threat to humanity. Biodiversity loss has been implicated as a central driver of the global increase in disease emergence, but the direction and mechanisms that connect biodiversity with disease emergence are controversial.Here we offer a novel perspective, hypothesizing that the loss of pathogen biodiversity may contribute to disease emergence risk. We posit that exposure to diverse related pathogens prompts hosts to establish multivalent cross-reactive antibody portfolios, which can (i) prevent severe disease, (ii) reduce transmission, and ultimately (iii) limit the risk of pathogen emergence. If true, these insights could be applied todesign multivalent "portfolio" vaccines, which can provide relatively stable protection against broad viral lineages. We willcombine mechanistic mathematical models with experimental and observational field studies to test these ideas, using East African nairoviruses as a model system, which include important animal (e.g. Nairobi Sheep Disease Virus, NSDV) and zoonotic (e.g. Crimean-Congo Haemorrhagic Fever Virus, CCHFV) pathogens.
Animal Health Component
30%
Research Effort Categories
Basic
70%
Applied
30%
Developmental
0%
Goals / Objectives
Infectious disease emergence is a clear and imminent threat to humanity. Anthropogenic biodiversity loss has been implicated as a central driver of the global increase in disease emergence, but the direction and mechanisms that connect biodiversity with disease emergence are controversial. Here we offer a novel perspective, hypothesizing that the loss of pathogen biodiversity may contribute to disease emergence risk. We posit that exposure to diverse related pathogens prompts hosts to establish multivalent cross-reactive antibody portfolios, which can (i) prevent severe disease, (ii) reduce transmission, and ultimately (iii) limit the risk of pathogen emergence. If true, these insights could be applied to (iv) design multivalent "portfolio" vaccines, which can provide relatively stable protection against broad viral lineages. We propose to combine mechanistic mathematical models with experimental and observational field studies to test these ideas, using East African nairoviruses as a model system, which include important animal (e.g. Nairobi Sheep Disease Virus, NSDV) and zoonotic (e.g. Crimean-Congo Haemorrhagic Fever Virus, CCHFV) pathogens.Specifically, we propose the following Aims:1. Conduct challenge experiments with NSDV in sheep to test whether prior exposure to related nairoviruses reduces transmission potential and disease severity in individual hosts.2. Create immune-epidemiological models to explore how within-host processes evaluated in Aim 1 scale up to shape patterns of infection in ticks, and disease in humans and livestock. Test model predictions with field surveys in Uganda.3. Use our modeling framework to investigate how nairoviral species richness affects viral genetic diversification and community invasibility. Test model predictions with experimental and field survey data from Aims 1 and 2.4. Pioneer proof-of-concept experiments in the NSDV / sheep model system to test the efficacy of "portfolio" vaccination in reducing disease severity and viral diversification.
Project Methods
Aim1: Conduct challenge experiments with NSDV in sheep, including assessment of disease severity and transmission of NSDV to tick vectors. Create within-host immune x pathogen kinetic modelsand fit to experimental data.Aim 2:Construct an immuno-epidemiological model.Survey nairovirus diversity, prevalence in tick vectors and human and livestock hosts in Uganda.Aim 3: We will leverage our sheep/NSDV model system (Aim 1) to address the hypothesis that prior exposure to related nairovirus antigens constrains the generation of NSDV genetic diversity in individual hosts using experimental work in sheep.We will use NSDV / CCHFV isolates collected during our cross-sectional survey across Uganda (Aim 2) to test whether within-lineage diversity of NSDV / CCHFV is negatively associated with nairovirus species diversity across sampling locations.Leveraging our multiscale immuno-epidemiological model of nairovirus infections (see Aim 2), we will use a trait-based adaptive dynamics approach, combining invasion analysis and numerical simulationto assess the invasibility of nairovirus communities of varying diversity, both in terms of the likelihood of successful establishment by a novel viral species, and the vulnerability of the host community to disease caused by the novel virus.Aim 4:We will extend the NSDV challenge study described in Aim 1 to include an additional group of sheep that have been exposed to antigens of three nairoviruses. Specifically, we will use co-exposure to antigens from CCHFV, DugbeV, and RVFV to explore the effect of antigen exposure diversity on severity and transmission potential during subsequent NSDV challenge