Gut Microbiota Composition Modulates the Magnitude and Quality of Germinal Centers during Plasmodium Infections

Abstract

SUMMARY Gut microbiota composition is associated with human and rodent Plasmodium infections, yet the mechanism by which gut microbiota affects the severity of malaria remains unknown. Humoral immunity is critical in mediating the clearance of Plasmodium blood stage infections, prompting the hypothesis that mice with gut microbiota-dependent decreases in parasite burden exhibit better germinal center (GC) responses. In support of this hypothesis, mice with a low parasite burden exhibit increases in GC B cell numbers and parasite-specific antibody titers, as well as better maintenance of GC structures and a more targeted, qualitatively different antibody response. This enhanced humoral immunity affects memory, as mice with a low parasite burden exhibit robust protection against challenge with a heterologous, lethal Plasmodium species. These results demonstrate that gut microbiota composition influences the biology of spleen GCs as well as the titer and repertoire of parasite-specific antibodies, identifying potential approaches to develop optimal treatments for malaria.

Observation of the Gut Microbiota Profile in C57BL/6 Mice Induced by Plasmodium berghei ANKA Infection

“…That is, HCM caused by P. falciparum might be associated with alterations in the gut microbiota. Consistent with this notion, a study revealed a remarkable association between the host microbiota composition and P. falciparum infection (Yooseph et al, 2015;Waide et al, 2020).…”

“…Malaria is a severe life-threatening disease with approximately 229 million clinical cases and 409,000 deaths in 2019 (WHO, 2020). Malaria has many economic burdens in addition to its health risks (Waide et al, 2020). Human malaria is caused by infection with four different Plasmodium parasites.…”

Dynamic modulation of spleen germinal center reactions by gut bacteria during Plasmodium infection

“…This suggests that vancomycin-induced decreases in parasitemia early during infection may be the result of changes in the quantity or quality of the P. yoelii-induced antibodies. In support of this possibility, we have shown that low parasite burden in mice mediated by gut microbiota composition is correlated with increased GC B cell numbers, parasite-specific antibody, better GC structure, and quality antibody response that also provided robust protection against lethal rodent Plasmodium challenge (Waide et al, 2020). Alternatively (Zhuang et al, 2019), the reduction in parasitemia following vancomycin treatment may have occurred through augmentation of other aspects of the host immune response.…”

“…(d7Van). Seven days after P. yoelii infection, by which time mice have induced GC responses (Figures 6D and 6E) (Waide et al, 2020), mice were treated with either an anti-CD40L monoclonal antibody (clone MR1) that disrupts GC reactions (Foy et al, 1993;Noelle et al, 1992) or an isotype control antibody (IgG) (Figure 6A). If vancomycin-induced changes in gut bacteria affect P. yoelii parasite burden independent of GC reactions, then disrupting GCs would have minimal effect on parasite burden in the vancomycintreated mice.…”

“…Another study, in which Malian children were longitudinally tracked from the end of the dry season (i.e., no malaria transmission) through the ensuing malaria transmission season, demonstrated a correlation between stool bacteria composition at the end of the dry season and rate at which children were infected with Plasmodium falciparum (Yooseph et al, 2015); for ethical reasons, this report did not assess severe malaria. Finally, the composition of gut microbiota has been shown to shape the severity of malaria in mice (Denny et al, 2019;Stough et al, 2016;Villarino et al, 2016) by fine-tuning the magnitude and quality of the humoral immune response to Plasmodium (Waide et al, 2020). Yet numerous knowledge gaps remain in understanding malaria-gut microbiome interactions.…”