Abstract
Mastitis is an inflammation of the mammary gland in the breast and is typically due to bacterial infection. In malaria-endemic areas, mastitis with accompanying fever can be challenging to differentiate from malaria. At the same time, it is unclear whether malaria infection is directly involved in the development of mastitis. In the present study, whether mastitis develops during infection with malaria parasites was investigated using a rodent malaria model with Plasmodium berghei (P. berghei; Pb) ANKA. The course of parasitemia in postpartum mice infected with Pb ANKA was similar to the course in infected virgin mice. However, infected postpartum mice died earlier than did infected virgin mice. In addition, the weight of pups from mice infected with Pb ANKA was significantly reduced compared with pups from uninfected mice. The macroscopic and histological analyses showed apparent changes, such as destruction of the alveolus wall and extensive presence of leukocytes, in mammary gland tissue in mice infected during the postpartum period. The findings suggest that women during the postpartum period are more vulnerable to complications when infected with malaria parasites, particularly women who do not acquire protective immunity against malaria parasites. Based on the proteomic analysis, IFN-γ signaling pathway-related proteins in mammary gland tissue of the infected postpartum mice were increased. Our results indicate that inflammation induced by IFN-γ, a proinflammatory cytokine, may contribute to negative histological changes in mammary gland tissue of postpartum mice infected with Pb ANKA. In IFN-γ receptor 1-deficient (IFNGR1-KO) mice, the histological changes in mammary gland tissue of the infected postpartum wild-type mice were improved to almost normal mammary gland structure. Furthermore, weight loss in pups delivered by infected IFNGR1-KO postpartum mice was not observed. Taken together, these findings indicate that inflammation induced by IFN-γ is associated with development of mastitis in postpartum mice infected with Pb ANKA. The present study results may increase our understanding of how disease aggravation occurs during postpartum malaria.
Highlights
Malaria is caused by the genus Plasmodium, and it is the major parasitic disease in tropical and subtropical regions [1]
The course of parasitemia in postpartum mice infected with Plasmodium berghei (Pb) ANKA was similar to the course in control mice, postpartum mice infected with malaria parasites developed mastitis, resulting in significantly reduced pup weight, compared with pups delivered by uninfected mice
The infected postpartum mice died earlier than did infected virgin mice. These findings indicated that the development of mastitis during infection with malaria parasites could occur during the postpartum period, in women who do not acquire protective immunity against malaria parasites
Summary
Malaria is caused by the genus Plasmodium, and it is the major parasitic disease in tropical and subtropical regions [1]. Five species of Plasmodium infect humans: P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi. P. falciparum causes severe pathologies such as cerebral and placental malaria in the blood stage. The courses of cerebral and placental malaria involve proinflammatory cytokines [5, 6]. In a study using a mouse model, dendritic cells activated via TLR signaling expand pathogenic CD4+ T cells and CD8+ T cells, as well as the production of proinflammatory cytokines (e.g., IFN-γ) [10]. In addition to pathogenic CD4+ T cells and CD8+ T cells, macrophages and neutrophils (via IFN-γ receptor 1 [IFNGR1]) cause development of cerebral and placental malaria [11,12,13,14]
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