Project Details
Description
ABSTRACT
Infections by parasites of the genus Plasmodium cause more than 200 million cases of malaria and kill more
than 400,000 people annually, most of whom are Plasmodium falciparum-infected children in sub-Saharan
Africa. The majority of P. falciparum infections are asymptomatic. While some infections progress to clinical
uncomplicated malaria (UM), a small percentage of infections progress to clinical forms of severe malaria (e.g.,
severe malarial anemia (SMA), cerebral malaria (CM)), which are responsible for P. falciparum related deaths.
To date, it is not fully understood what factors contribute towards the susceptibility of P. falciparum infection
progressing to clinical UM or severe malaria. Gut microbiota provide many benefits to the host, including
modulation of host immunity. In a murine model system, we recently published that mice with distinct gut
bacterial communities exhibit differences in the severity of malaria and humoral immunity following infection.
Mice with a specific bacterial community profile developed relatively low parasitemia following Plasmodium
yoelii infection and exhibited elevated T follicular helper (Tfh) and germinal center (GC) B cell numbers and
accelerated antibody class switching compared to mice with a different bacterial community profile that
developed high parasitemia. When mice that develop low parasitemia were treated with antibodies that disrupt
Tfh-GC B cell communication, they had similarly high parasite burdens as control mice. These findings suggest
that microbiome-mediated modulation of the GC reaction may be a mechanism underlying the development of
severe malaria. Currently, there are no definitive human data on the effect of the gut microbiome on the
progression of P. falciparum infection to clinical malaria. Of note, our preliminary data demonstrate that
children with asymptomatic parasitemia (AP) infections have different stool bacteria communities than children
with SMA, and prospective analysis of stool bacteria in Malian children has identified significant differences
between children who maintain or control AP infection versus children who develop febrile malaria. These
novel findings support the central hypothesis that the composition of gut microbiota in humans is a risk factor
for developing clinical malaria through modulation of GC reactions. Our hypothesis will be tested through the
following specific aims: Aim 1. Demonstrate the human gut microbiome is capable of causing differential
susceptibility to malaria. Aim 2. Determine the role of human gut microbiota in modulating GC reactions
following Plasmodium infection.
Status | Finished |
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Effective start/end date | 7/1/20 → 6/30/23 |
Funding
- National Institute of Allergy and Infectious Diseases: $741,463.00
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