Resistance to Acute Babesiosis Is Associated with Interleukin-12- and Gamma Interferon-Mediated Responses and Requires Macrophages and Natural Killer Cells

Abstract

We examined the role of the cytokines gamma interferon (IFN-γ) and interleukin-12 (IL-12) in the model of acute babesiosis with the WA1 Babesia. Mice genetically deficient in IFN-γ-mediated responses (IFNGR2KO mice) and IL-12-mediated responses (Stat4KO mice) were infected with the WA1 Babesia, and observations were made on the course of infection and cytokine responses. Levels of IFN-γ and IL-12 in serum increased 24 h after parasite inoculation. The augmented susceptibility observed in IFNGR2KO and Stat-4KO mice suggests that the early IL-12- and IFN-γ-mediated responses are involved in protection against acute babesiosis. Resistance appears to correlate with an increase in nitric oxide (NO) production. In order to assess the contribution of different cell subsets to resistance against the parasite, we also studied mice lacking B cells, CD4+ T cells, NK cells, and macrophages. Mice genetically deficient in B lymphocytes or CD4+ T lymphocytes were able to mount protective responses comparable to those of immunosufficient mice. In contrast, in vivo depletion of macrophages or NK cells resulted in elevated susceptibility to the infection. Our observations suggest that a crucial part of the response that protects from the pathogenic Babesia WA1 is mediated by macrophages and NK cells, probably through early production of IL-12 and IFN-γ, and induction of macrophage-derived effector molecules like NO

Both Viral and Host Factors Contribute to Neurovirulence of Bovine Herpesviruses 1 and 5 in Interferon Receptor-Deficient Mice

“…However, compared to that in AGR129 mice, the onset of the disease symptoms in BHV-5-infected AR129 mice was delayed by at least 5 days. Thus, it seemed as if the gamma interferon system, supported by activated NK cells (2,18,45), was able to protect mice from BHV-1-associated disease and death. In contrast, the same elements appeared to be unable to protect AR129 mice from BHV-5-associated disease.…”

Macrophages Are Critical for Cross-Protective Immunity Conferred by Babesia microti against Babesia rodhaini Infection in Mice

“…In general, successful resolution of rodent Babesia is dependent on the ability of mice to mount an early proinflammatory cytokine response (IL-12 and IFN-␥) and the appropriate maintenance of their kinetics during acute stage of infection, thereby preventing the parasitemia from escalating to overwhelming levels. During the resolution stage, the predominance of these cytokines shifts to the Th2-based cytokines IL-4 and IL-10 accompanied by IgG responses (2,27). Therefore, the rapid proliferation of B. rodhaini in mice might be due to the early elevation of an anti-inflammatory cytokine (IL-10) that inhibits the activity of Th1 cells, NK cells, and macrophages, thereby preventing the resolution of the infection (21).…”

“…Better knowledge of the host immune response to Babesia infection is undoubtedly needed to achieve this (11,27). Rodent babesiosis has been widely utilized as an experimental model to investigate the host immune response to Babesia infection (2,50). The causative agents of babesiosis in rodent are B. microti and B. rodhaini, which cause different diseases in mice.…”

“…Moreover, the failure to maintain Th1-predominant response during the acute stage is correlated with a rapid increase in parasite load. On the other hand, the switch to the predominance of the Th2 response (IL-4 and IL-10) at the resolution stage accompanied by elevated antigen-specific immunoglobulin G (IgG) appears to be crucial for the control of parasite replication (2,12). Phagocytosis of parasitized erythrocytes by activated macrophages occurs in the spleen and is believed to be essential for the removal of the parasites (48).…”

“…Over the past decade, several studies have demonstrated the importance of T helper (Th) cells in regulating the immune response to Babesia infection (2,12,28). These cells produce the cytokines needed for the both maturation of high-affinity immunoglobulin isotype production and the activation of macrophages for phagocytosis and parasiticidal activity (10,11).…”