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

Artemis Efstratiou,Yoshifumi Nishikawa,Hiroshi Suzuki,Eloiza May S Galon,Daisuke Kondoh,Aaron Edmond Ringo,Ikuo Igarashi,Mohamad Alaa Terkawi,Seung-Hun Lee,Huanping Guo,Yang Gao,Guanbo Wang,Jixu Li,Xuenan Xuan,Kousuke Umeda,Aiko Kume,Paul Franck Adjou Moumouni,Mingming Liu

doi:10.3389/fcimb.2020.00193

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.

Highlights

Malaria persists as one of the biggest global health burdens, despite continuous attempts for its elimination and eradication
To determine whether co-infection and various stages of B. microti infection can protect against a lethal P. chabaudi challenge, mice were initially injected with B. microti, challenged with P. chabaudi at different time points: simultaneously with B. microti, at the acute stage, at the resolving stage, and at the chronic stage of primary B. microti infection
Immunofluorescence Antibody Test (IFAT) for parasitized RBCs (pRBCs) collected 6 days after the P. chabaudi challenge infection from mice chronically infected with B. microti revealed that most pRBCs were infected with P. chabaudi, low numbers of B. microti-pRBCs were still observable (Supplementary Figure 2)

Summary

Introduction

Malaria persists as one of the biggest global health burdens, despite continuous attempts for its elimination and eradication. Plasmodium parasites, the malaria-causing agents, are still endemic in 91 countries and cause over 200 million infection cases every year (World Health Organization., 2016). The host immune response to Plasmodium has been a research focal point for decades, as a deeper understanding of the underlying infection mechanism constitutes a major prerequisite for the development of an efficient vaccine. Major strides have been made by malaria researchers toward elucidating the infection and replication machinery of Plasmodium. This has been a challenging task, largely due to the complex life cycle of the parasite within the host, which results in the immune system being confronted with multiple morphologically distinct phases of infection- both intracellular and extracellular. It is generally accepted that both humoral and cellular immune responses are required for successful parasite elimination (Langhorne et al, 2002)

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Conclusion