Research in the Brook Lab uses 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

batBats 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

bat_cell 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.



 

Deciphering links between disease and aging

bat_popIn addition to their unique viral tolerance, bats bost lifespans some 3.5x longer than those of any other mammalian group. Evidence suggests that unique molecular mechanisms evolved to enable flight have had cascading consequences on both bats’ viral tolerance and their extraordinary longevity. In collaboration with the Sudmant Lab at UC Berkeley, we are launching new work, both in the field and in tissue culture elucidating links between anti-aging pathways and disease resilience in bat hosts for emerging human diseases. Funding from the Branco Weiss ‘Society in Science’ Fellowship will support this exciting new work, including the development of new techniques for aging wild-caught Madagascar fruit bats via epigenetics.

 

Conservation biology and population modeling

baby_batUsing age data derived from fruit bat dentition (though see above for novel, less invasive methods of aging in development), 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, tenrecs, and the ploughshare tortoise.


 

Next Generation Sequencing to decipher the etiology of unexplained human fevers

chris_czb Our lab was recently 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 are currently undertaking sequencing of bat excretia from our longitudinal study concurrently with sequencing of samples from undiagnosed febrile human patients reporting to public hospitals across Madagascar. Our goal is to describe the landscape of potential viral zoonoses in biological samples from wild bats and identify any bat-derived zoonotic viruses responsible for human fever in Madagascar.

 

COVID-19 phylodynamics in Madagascar

Mada_SC2 Madagascar reported its first case of COVID-19 on March 20, 2020 and has since diagnosed several more than 16,000 cases of COVID-19 from just under 80,000 tests (daily updated data available at COVID-19 Madagascar Dashboard). Our lab recently received support from UC Berkeley’s Innovative Genomics Institute to use the NGS tools outlined above at IPM to sequence SARS-CoV-2, the causative agent in COVID-19, in Madagascar. Our main goals are to use these sequence data to: [1] Estimate timing of the origin of the COVID-19 epidemic in Madagascar, [2] Estimate the underreporting rate of qPCR-based positive case counts in Madagascar, and [3] Decipher patterns of cross-island connectivity and community spread across the island. We have recently released the two first sequences of SARS-COV-2 from human cases in Madagascar to GISAID, and they are available for viewing on Nextstrain. Stay tuned for more mechanistic insights as we expand our sequencing efforts soon!