Browsing by Author "Denny, Joshua E."

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    Dynamic modulation of spleen germinal center reactions by gut bacteria during Plasmodium infection
    (Cell Press, 2021-05-11) Mandal, Rabindra K.; Denny, Joshua E.; Namazzi, Ruth; Opoka, Robert O.; Datta, Dibyadyuti; John, Chandy C.; Schmidt, Nathan W.; Pediatrics, School of Medicine
    Gut microbiota educate the local and distal immune system in early life to imprint long-term immunological outcomes while maintaining the capacity to dynamically modulate the local mucosal immune system throughout life. It is unknown whether gut microbiota provide signals that dynamically regulate distal immune responses following an extra-gastrointestinal infection. We show here that gut bacteria composition correlated with the severity of malaria in children. Using the murine model of malaria, we demonstrate that parasite burden and spleen germinal center reactions are malleable to dynamic cues provided by gut bacteria. Whereas antibiotic-induced changes in gut bacteria have been associated with immunopathology or impairment of immunity, the data demonstrate that antibiotic-induced changes in gut bacteria can enhance immunity to Plasmodium. This effect is not universal but depends on baseline gut bacteria composition. These data demonstrate the dynamic communications that exist among gut bacteria, the gut-distal immune system, and control of Plasmodium infection.
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    Gut Bacteroides act in a microbial consortium to cause susceptibility to severe malaria
    (Springer, 2023-10-13) Mandal, Rabindra K.; Mandal, Anita; Denny, Joshua E.; Namazii, Ruth; John, Chandy C.; Schmidt, Nathan W.; Pediatrics, School of Medicine
    Malaria is caused by Plasmodium species and remains a significant cause of morbidity and mortality globally. Gut bacteria can influence the severity of malaria, but the contribution of specific bacteria to the risk of severe malaria is unknown. Here, multiomics approaches demonstrate that specific species of Bacteroides are causally linked to the risk of severe malaria. Plasmodium yoelii hyperparasitemia-resistant mice gavaged with murine-isolated Bacteroides fragilis develop P. yoelii hyperparasitemia. Moreover, Bacteroides are significantly more abundant in Ugandan children with severe malarial anemia than with asymptomatic P. falciparum infection. Human isolates of Bacteroides caccae, Bacteroides uniformis, and Bacteroides ovatus were able to cause susceptibility to severe malaria in mice. While monocolonization of germ-free mice with Bacteroides alone is insufficient to cause susceptibility to hyperparasitemia, meta-analysis across multiple studies support a main role for Bacteroides in susceptibility to severe malaria. Approaches that target gut Bacteroides present an opportunity to prevent severe malaria and associated deaths.
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    Gut Bacteroides act in a microbial consortium to cause susceptibility to severe malaria
    (Springer Nature, 2023-10-13) Mandal, Rabindra K.; Mandal, Anita; Denny, Joshua E.; Namazii, Ruth; John, Chandy C.; Schmidt, Nathan W.; Pediatrics, School of Medicine
    Malaria is caused by Plasmodium species and remains a significant cause of morbidity and mortality globally. Gut bacteria can influence the severity of malaria, but the contribution of specific bacteria to the risk of severe malaria is unknown. Here, multiomics approaches demonstrate that specific species of Bacteroides are causally linked to the risk of severe malaria. Plasmodium yoelii hyperparasitemia-resistant mice gavaged with murine-isolated Bacteroides fragilis develop P. yoelii hyperparasitemia. Moreover, Bacteroides are significantly more abundant in Ugandan children with severe malarial anemia than with asymptomatic P. falciparum infection. Human isolates of Bacteroides caccae, Bacteroides uniformis, and Bacteroides ovatus were able to cause susceptibility to severe malaria in mice. While monocolonization of germ-free mice with Bacteroides alone is insufficient to cause susceptibility to hyperparasitemia, meta-analysis across multiple studies support a main role for Bacteroides in susceptibility to severe malaria. Approaches that target gut Bacteroides present an opportunity to prevent severe malaria and associated deaths.
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    Gut Microbiota Composition Modulates the Magnitude and Quality of Germinal Centers during Plasmodium Infections
    (Cell Press, 2020-12-15) Waide, Morgan L.; Polidoro, Rafael; Powell, Whitney L.; Denny, Joshua E.; Kos, Justin; Tieri, David A.; Watson, Corey T.; Schmidt, Nathan W.; Pediatrics, School of Medicine
    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.
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    Oral Administration of Clinically Relevant Antimalarial Drugs Does Not Modify the Murine Gut Microbiota
    (Springer Nature, 2019-08-16) Denny, Joshua E.; Schmidt, Nathan W.; Microbiology and Immunology, School of Medicine
    Malaria is an infectious disease responsible for the death of around 450,000 people annually. As an effective vaccine against the parasite that causes malaria is not available, antimalarial drug treatments are critical in fighting the disease. Previous data has shown that the gut microbiota is important in modulating the severity of malaria. Although it is well appreciated that antibiotics substantially alter the gut microbiota, it is largely unknown how antimalarial drugs impact the gut microbiota. We show here that the two commonly used artemisinin combination therapies of artesunate plus amodiaquine and artemether plus lumefantrine do not change the gut microbiota. The overall relative species abundance and alpha diversity remained stable after treatment, while beta diversity analysis showed minimal changes due to drug treatment, which were transient and quickly returned to baseline. Additionally, treatment with antimalarial drugs did not change the kinetics of later Plasmodium infection. Taken together, antimalarial drug administration does not affect the gut microbiota.
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    Temporospatial shifts within commercial laboratory mouse gut microbiota impact experimental reproducibility
    (BMC, 2020-07-03) Mandal, Rabindra K.; Denny, Joshua E.; Waide, Morgan L.; Li, Qingsheng; Bhutiani, Neal; Anderson, Charles D.; Baby, Becca V.; Jala, Venkatakrishna R.; Egilmez, Nejat K.; Schmidt, Nathan W.; Pediatrics, School of Medicine
    Experimental reproducibility in mouse models is impacted by both genetics and environment. The generation of reproducible data is critical for the biomedical enterprise and has become a major concern for the scientific community and funding agencies alike. Among the factors that impact reproducibility in experimental mouse models is the variable composition of the microbiota in mice supplied by different commercial vendors. Less attention has been paid to how the microbiota of mice supplied by a particular vendor might change over time. Results In the course of conducting a series of experiments in a mouse model of malaria, we observed a profound and lasting change in the severity of malaria in mice infected with Plasmodium yoelii; while for several years mice obtained from a specific production suite of a specific commercial vendor were able to clear the parasites effectively in a relatively short time, mice subsequently shipped from the same unit suffered much more severe disease. Gut microbiota analysis of frozen cecal samples identified a distinct and lasting shift in bacteria populations that coincided with the altered response of the later shipments of mice to infection with malaria parasites. Germ-free mice colonized with cecal microbiota from mice within the same production suite before and after this change followed by Plasmodium infection provided a direct demonstration that the change in gut microbiota profoundly impacted the severity of malaria. Moreover, spatial changes in gut microbiota composition were also shown to alter the acute bacterial burden following Salmonella infection, and tumor burden in a lung tumorigenesis model. Conclusion These changes in gut bacteria may have impacted the experimental reproducibility of diverse research groups and highlight the need for both laboratory animal providers and researchers to collaborate in determining the methods and criteria needed to stabilize the gut microbiota of animal breeding colonies and research cohorts, and to develop a microbiota solution to increase experimental rigor and reproducibility.