Heterogeneity of Rift Valley fever virus transmission potential across livestock hosts, quantified through a model-based analysis of host viral load and vector infection.

Quantifying the variation of pathogens' life history traits in multiple host systems is crucial to understand their transmission dynamics. It is particularly important for arthropod-borne viruses (arboviruses), which are prone to infecting several species of vertebrate hosts. Here, we focus on how host-pathogen interactions determine the ability of host species to transmit a virus to susceptible vectors upon a potentially infectious contact. Rift Valley fever (RVF) is a viral, vector-borne, zoonotic disease, chosen as a case study. The relative contributions of livestock species to RVFV transmission has not been previously quantified. To estimate their potential to transmit the virus over the course of their infection, we 1) fitted a within-host model to viral RNA and infectious virus measures, obtained daily from infected lambs, calves, and young goats, 2) estimated the relationship between vertebrate host infectious titers and probability to infect mosquitoes, and 3) estimated the net infectiousness of each host species over the duration of their infectious periods, taking into account different survival outcomes for lambs. Our results indicate that the efficiency of viral replication, along with the lifespan of infectious particles, could be sources of heterogeneity between hosts. Given available data on RVFV competent vectors, we found that, for similar infectious titers, infection rates in the Aedes genus were on average higher than in the Culex genus. Consequently, for Aedes-mediated infections, we estimated the net infectiousness of lambs to be 2.93 (median) and 3.65 times higher than that of calves and goats, respectively. In lambs, we estimated the overall infectiousness to be 1.93 times higher in individuals which eventually died from the infection than in those recovering. Beyond infectiousness, the relative contributions of host species to transmission depend on local ecological factors, including relative abundances and vector host-feeding preferences. Quantifying these contributions will ultimately help design efficient, targeted, surveillance and vaccination strategies.

Dispersal in heterogeneous environments drives population dynamics and control of tsetse flies.

Spatio-temporally heterogeneous environments may lead to unexpected population dynamics. Knowledge is needed on local properties favouring population resilience at large scale. For pathogen vectors, such as tsetse flies transmitting human and animal African trypanosomosis, this is crucial to target management strategies. We developed a mechanistic spatio-temporal model of the age-structured population dynamics of tsetse flies, parametrized with field and laboratory data. It accounts for density- and temperature-dependence. The studied environment is heterogeneous, fragmented and dispersal is suitability-driven. We confirmed that temperature and adult mortality have a strong impact on tsetse populations. When homogeneously increasing adult mortality, control was less effective and induced faster population recovery in the coldest and temperature-stable locations, creating refuges. To optimally select locations to control, we assessed the potential impact of treating them and their contribution to the whole population. This heterogeneous control induced a similar population decrease, with more dispersed individuals. Control efficacy was no longer related to temperature. Dispersal was responsible for refuges at the interface between controlled and uncontrolled zones, where resurgence after control was very high. The early identification of refuges, which could jeopardize control efforts, is crucial. We recommend baseline data collection to characterize the ecosystem before implementing any measures.

Aedes albopictus is not an arbovirus aficionado - Impacts of sylvatic flavivirus infection in vectors and hosts on mosquito engorgement on non-human primates.

The contact structure between vertebrate hosts and arthropod vectors plays a key role in the spread of arthropod-borne viruses (arboviruses); thus, it is important to determine whether arbovirus infection of either host or vector alters vector feeding behavior. Here we leveraged a study of the replication dynamics of two arboviruses isolated from their ancestral cycles in paleotropical forests, sylvatic dengue-2 (DENV-2) and Zika (ZIKV), in one non-human primate (NHP) species from the paleotropics (cynomolgus macaques, Macaca fascicularis) and one from the neotropics (squirrel monkeys, Saimiri boliviensis) to test the effect of both vector and host infection with each virus on completion of blood feeding (engorgement) of the mosquito Aedes albopictus. Although mosquitoes were starved and given no choice of hosts, engorgement rates varied dramatically, from 0% to 100%. While neither vector nor host infection systematically affected engorgement, NHP species and body temperature at the time of feeding did. We also interrogated the effect of repeated mosquito bites on cytokine expression and found that epidermal growth factor (EGF) and macrophage migration inhibitory factor (MIF) concentrations were dynamically associated with exposure to mosquito bites. This study highlights the importance of incorporating individual-level heterogeneity of vector biting in arbovirus transmission models.

Trade-offs shaping transmission of sylvatic dengue and Zika viruses in monkey hosts.

Mosquito-borne dengue (DENV) and Zika (ZIKV) viruses originated in Old World sylvatic (forest) cycles involving monkeys and canopy-living Aedes mosquitoes. Both viruses spilled over into human transmission and were translocated to the Americas, opening a path for spillback into Neotropical sylvatic cycles. Studies of the trade-offs that shape within-host dynamics and transmission of these viruses are lacking, hampering efforts to predict spillover and spillback. We infected a native, Asian host species (cynomolgus macaque) and a novel, American host species (squirrel monkey) with sylvatic strains of DENV-2 or ZIKV via mosquito bite. We then monitored aspects of viral replication (viremia), innate and adaptive immune response (natural killer (NK) cells and neutralizing antibodies, respectively), and transmission to mosquitoes. In both hosts, ZIKV reached high titers that translated into high transmission to mosquitoes; in contrast DENV-2 replicated to low levels and, unexpectedly, transmission occurred only when serum viremia was below or near the limit of detection. Our data reveal evidence of an immunologically-mediated trade-off between duration and magnitude of virus replication, as higher peak ZIKV titers are associated with shorter durations of viremia, and higher NK cell levels are associated with lower peak ZIKV titers and lower anti-DENV-2 antibody levels. Furthermore, patterns of transmission of each virus from a Neotropical monkey suggest that ZIKV has greater potential than DENV-2 to establish a sylvatic transmission cycle in the Americas.

Immunologically mediated trade-offs shaping transmission of sylvatic dengue and Zika viruses in native and novel non-human primate hosts.

Mosquito-borne dengue (DENV) and Zika (ZIKV) viruses originated in Old World sylvatic cycles involving monkey hosts, spilled over into human transmission, and were translocated to the Americas, creating potential for spillback into neotropical sylvatic cycles. Studies of the trade-offs that shape within-host dynamics and transmission of these viruses are lacking, hampering efforts to predict spillover and spillback. We exposed native (cynomolgus macaque) or novel (squirrel monkey) hosts to mosquitoes infected with either sylvatic DENV or ZIKV and monitored viremia, natural killer cells, transmission to mosquitoes, cytokines, and neutralizing antibody titers. Unexpectedly, DENV transmission from both host species occurred only when serum viremia was undetectable or near the limit of detection. ZIKV replicated in squirrel monkeys to much higher titers than DENV and was transmitted more efficiently but stimulated lower neutralizing antibody titers. Increasing ZIKV viremia led to greater instantaneous transmission and shorter duration of infection, consistent with a replication-clearance trade-off.

Mechanistic models of Rift Valley fever virus transmission: A systematic review.

Rift Valley fever (RVF) is a zoonotic arbovirosis which has been reported across Africa including the northernmost edge, South West Indian Ocean islands, and the Arabian Peninsula. The virus is responsible for high abortion rates and mortality in young ruminants, with economic impacts in affected countries. To date, RVF epidemiological mechanisms are not fully understood, due to the multiplicity of implicated vertebrate hosts, vectors, and ecosystems. In this context, mathematical models are useful tools to develop our understanding of complex systems, and mechanistic models are particularly suited to data-scarce settings. Here, we performed a systematic review of mechanistic models studying RVF, to explore their diversity and their contribution to the understanding of this disease epidemiology. Researching Pubmed and Scopus databases (October 2021), we eventually selected 48 papers, presenting overall 49 different models with numerical application to RVF. We categorized models as theoretical, applied, or grey, depending on whether they represented a specific geographical context or not, and whether they relied on an extensive use of data. We discussed their contributions to the understanding of RVF epidemiology, and highlighted that theoretical and applied models are used differently yet meet common objectives. Through the examination of model features, we identified research questions left unexplored across scales, such as the role of animal mobility, as well as the relative contributions of host and vector species to transmission. Importantly, we noted a substantial lack of justification when choosing a functional form for the force of infection. Overall, we showed a great diversity in RVF models, leading to important progress in our comprehension of epidemiological mechanisms. To go further, data gaps must be filled, and modelers need to improve their code accessibility.

Over 100 Years of Rift Valley Fever: A Patchwork of Data on Pathogen Spread and Spillover.

During the past 100 years, Rift Valley fever virus (RVFV), a mosquito-borne virus, has caused potentially lethal disease in livestock, and has been associated with significant economic losses and trade bans. Spillover to humans occurs and can be fatal. Here, we combined data on RVF disease in humans (22 countries) and animals (37 countries) from 1931 to 2020 with seroprevalence studies from 1950 to 2020 (n = 228) from publicly available databases and publications to draw a more complete picture of the past and current RVFV epidemiology. RVFV has spread from its original locus in Kenya throughout Africa and into the Arabian Peninsula. Throughout the study period seroprevalence increased in both humans and animals, suggesting potentially increased RVFV exposure. In 24 countries, animals or humans tested positive for RVFV antibodies even though outbreaks had never been reported there, suggesting RVFV transmission may well go unnoticed. Among ruminants, sheep were the most likely to be exposed during RVF outbreaks, but not during periods of cryptic spread. We discuss critical data gaps and highlight the need for detailed study descriptions, and long-term studies using a one health approach to further convert the patchwork of data to the tale of RFV epidemiology.

It's risky to wander in September: Modelling the epidemic potential of Rift Valley fever in a Sahelian setting.

Estimating the epidemic potential of vector-borne diseases, along with the relative contribution of underlying mechanisms, is crucial for animal and human health worldwide. In West African Sahel, several outbreaks of Rift Valley fever (RVF) have occurred over the last decades, but uncertainty remains about the conditions necessary to trigger these outbreaks. We use the basic reproduction number (R0) as a measure of RVF epidemic potential in northern Senegal, and map its value in two distinct ecosystems, namely the Ferlo and the Senegal River delta and valley. We consider three consecutive rainy seasons (July-November 2014, 2015 and 2016) and account for several vector and animal species. We parametrize our model with estimates of Aedes vexans arabiensis, Culex poicilipes, Culex tritaeniorhynchus, cattle, sheep and goat abundances. The impact of RVF virus introduction is assessed every week over northern Senegal. We highlight September as the period of highest epidemic potential in northern Senegal, resulting from distinct dynamics in the two study areas. Spatially, in the seasonal environment of the Ferlo, we observe that high-risk locations vary between years. We show that decreased vector densities do not greatly reduce R0 and that cattle immunity has a greater impact on reducing transmission than small ruminant immunity. The host preferences of vectors and the temperature-dependent time interval between their blood meals are crucial parameters needing further biological investigations.