Research

We use tools derived from field biology, molecular immunology, and epidemiological modeling to study how zoonotic pathogens persist, transmit, and evolve in wild reservoir and spillover human hosts. Much of our work is focused on zoonotic infections derived from bat reservoirs, and we conduct the majority of our field studies in Madagascar. Major areas of research in the lab are summarized below.

Bats as reservoirs for emerging viral zoonoses

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Bats are reservoir hosts for the world’s most virulent emerging viral zoonoses, including Hendra and Nipah henipaviruses, Ebola and Marburg filoviruses, and SARS, MERS, and SARS-CoV-2 coronaviruses. The Brook Lab investigates how these pathogens which manifest as highly virulent in humans are maintained at the population-level in wild bat reservoir hosts. Classic epidemiological modeling explores the dynamics of perfectly immunizing childhood infections, under which hosts are born susceptible (S), become infectious (I), and recover (R) via immune responses retained for life. In the simplest example, infections persist maintained in a population by constant re-supply of susceptible births. Many bat species reproduce in annual or biannual birth pulses, meaning that susceptible re-supply is restricted within a year. Such a system suggests that bat viruses may be governed by more nuanced dynamics than standard SIR–be they longer infectious periods, latent periods for persistent infections, or periodic waning immunity. To elucidate these dynamics, we fit candidate mechanistic models to age-structured prevalence and seroprevalence data, which we collect ourselves through the field studies of the inimitable Ekipa Fanihy. This work is funded through an NIH capacity-building grant in partnership with the Institut Pasteur of Madagascar (IPM).

 

The coevolution of bats and viruses

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Bats appear to host otherwise virulent viral infections without themselves experiencing substantial pathology. Accumulating molecular evidence links the evolution of flight to bat viral tolerance: unique anti-inflammatory pathways in bat immune systems enable them to avoid oxidative damage accrued during the metabolically expensive process of flight, with cascading consequences for bat longevity and resilience to intracellular infections. Bats’ abilities to host viruses without disease may provide selective pressure for the evolution of pathogens which are not virulent to their bat hosts but cause extreme disease uponn spillover to non-bat (i.e. human) hosts. We use a combination of experiments carried out in bat cell tissue culture and theoretical models to investigate the co-evolution of bat immune systems and their pathogens. On average, we have shown that bat-borne zoonoses cause higher human case fatality rates than do viruses derived from any other mammalian group.

 

Conservation biology and population modeling

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Using age data derived from fruit bat dentition, we have undertaken population modeling studies for wild, Madagascar fruit bats. These studies suggest that the Madagascar Flying Fox, Pteropus rufus, is particularly threatened by habitat destruction and human hunting for food consumption in Madagascar. We are currently working with a local conservation NGO, Madigasikara Voakajy, to develop conservation-oriented intervention plans for this species and undertaking new studies aimed at quantifying the positive benefits that this bat offers to healthy ecosystems, including pollination of several endangered Malagasy baobab species. We are also involved in several other conservation collaborations, through which we have undertaken population modeling for several non-Chiropteran threatened taxa, including endemic Malagasy lemurs and tenrecs.

 

Next Generation Sequencing for public health in Madagascar

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Our lab was awarded a Bill & Melinda Gates Foundation Grand Challenges Explorations grant for ‘Metagenomic Next Generation Sequencing for Pathogen Identification in Low-Income Countries.’ In part with this award, Malagasy colleagues from the IPM trained in library preparation and metagenomic Next Generation Sequencing at Chan Zuckerberg Biohub (San Francisco, CA) in July 2019. In March 2020, we received an Illumina sequencing machine at IPM and, with additional support from the UC Berkeley Innovative Genomics Institute, we have been using it to carry out genomic surveillance for SARS-CoV-2 variants of concern in Madagascar. In the past year, we have contributed over 700 genomes to the global genome repository, GISAID. In the future, we hope to use the iSeq to carry out concurrent sequencing of bat excretia from our longitudinal study along with sequencing of samples from undiagnosed febrile human patients reporting to public hospitals across Madagascar.