Babesia microti Confers Macrophage-Based Cross-Protective Immunity Against Murine Malaria

Abstract

Malaria and babesiosis, the two primary intraerythrocytic protozoan diseases of humans, have been reported in multiple cases of co-infection in endemic regions. As the geographic range and incidence of arthropod-borne infectious diseases is being affected by climate change, co-infection cases with Plasmodium and Babesia are likely to increase. The two parasites have been used in experimental settings, where prior infection with Babesia microti has been shown to protect against fatal malarial infections in mice and primates. However, the immunological mechanisms behind such phenomena of cross-protection remain unknown. Here, we investigated the effect of a primary B. microti infection on the outcome of a lethal P. chabaudi challenge infection using a murine model. Simultaneous infection with both pathogens led to high mortality rates in immunocompetent BALB/c mice, similar to control mice infected with P. chabaudi alone. On the other hand, mice with various stages of B. microti primary infection were thoroughly immune to a subsequent P. chabaudi challenge. Protected mice exhibited decreased levels of serum antibodies and pro-inflammatory cytokines during early stages of challenge infection. Mice repeatedly immunized with dead B. microti quickly succumbed to P. chabaudi infection, despite induction of high antibody responses. Notably, cross-protection was observed in mice lacking functional B and T lymphocytes. When the role of other innate immune effector cells was examined, NK cell-depleted mice with chronic B. microti infection were also found to be protected against P. chabaudi. Conversely, in vivo macrophage depletion rendered the mice vulnerable to P. chabaudi. The above results show that the mechanism of cross-protection conferred by B. microti against P. chabaudi is innate immunity-based, and suggest that it relies predominantly upon the function of macrophages. Further research is needed for elucidating the malaria-suppressing effects of babesiosis, with a vision toward development of novel tools to control malaria.

Serine proteases profiles of Leishmania (Viannia) braziliensis clinical isolates with distinct susceptibilities to antimony

“…In this context, genome plasticity of Leishmania spp. with frequent copy number variations of genes or chromosomes, as well as recombination events, increases their diversity and biological capacity to expand under different stress conditions 33 – 35 .…”

Lessons Learned for Pathogenesis, Immunology, and Disease of Erythrocytic Parasites: Plasmodium and Babesia

“…Both cellular and humoral immune responses are significantly induced during Babesia and Plasmodium infection. Antibodies block Plasmodium merozoite invasion of erythrocytes; however, they do not appear to significantly promote opsonophagocytosis of iRBCs of either Babesia or Plasmodium ( Moreau et al., 2015 ; Arora et al., 2018 ; Akter et al., 2019 ; Kochayoo et al., 2019 ; Oyong et al., 2019 ; Efstratiou et al., 2020 ). Therefore, humoral immunity appears to play a minor role in resolving the parasitemia of these parasites.…”

“…Antibody participation is not essential for offering cross-protection against other hemoparasites. Infection of mice with B. microti could protect mice against a follow-up fatal infection by B. rodhaini ( Efstratiou et al., 2020 ) by reducing parasitemia levels. Surprisingly, significant reduction in the level of antibodies was observed in the protected mice, and levels of cytokines including IFNγ, IL-2, IL-8, IL-10, and IL-12, and of nitric oxide after infection with B. rodhaini also diminished.…”

“…Notably, cross-protection was also observed in mice lacking functional B and T lymphocytes. On examination of the other innate immune effector cells, mice depleted of NK cells showing chronic B. microti infection were also protected from P. chabaudi infection ( Efstratiou et al., 2020 ). In contrast, in vivo depletion of macrophages in mice made them susceptible to P. chabaudi .…”

Congenital Transmission of Apicomplexan Parasites: A Review

“…However, it has been suggested that proinflammatory cytokine activation and erythrocyte adhesion in babesiosis are similar to malaria (Krause et al, 2007;Figure 2B). Some studies have even documented that prior infection with B. microti protects against fatal malaria in mice and primates through a mechanism of cross-protection (van Duivenvoorde et al, 2010;Efstratiou et al, 2020).…”