Gamma Interferon Production Is Critical for Protective Immunity to Infection with Blood-StagePlasmodium bergheiXAT but Neither NO Production nor NK Cell Activation Is Critical

Abstract

We have examined the roles of gamma interferon (IFN-γ), nitric oxide (NO), and natural killer (NK) cells in the host resistance to infection with the blood-stage malarial parasite Plasmodium berghei XAT, an irradiation-induced attenuated variant of the lethal strain P. berghei NK65. Although the infection withP. berghei XAT enhanced NK cell lytic activity of splenocytes, depletion of NK1.1+ cells caused by the treatment of mice with anti-NK1.1 antibody affected neither parasitemia nor IFN-γ production by their splenocytes. The P. bergheiXAT infection induced a large amount of NO production by splenocytes during the first peak of parasitemia, while P. berghei NK65 infection induced a small amount. Unexpectedly, however, mice deficient in inducible nitric oxide synthase (iNOS−/−) clearedP. berghei XAT after two peaks of parasitemia were observed, as occurred for wild-type control mice. Although the infected iNOS−/− mouse splenocytes did not produce a detectable level of NO, they produced an amount of IFN-γ comparable to that produced by wild-type control mouse splenocytes, and treatment of these mice with neutralizing anti-IFN-γ antibody led to the progression of parasitemia and fatal outcome. CD4−/− mice infected withP. berghei XAT could not clear the parasite, and all these mice died with apparently reduced IFN-γ production. Furthermore, treatment with carrageenan increased the susceptibility of mice toP. berghei XAT infection. These results suggest that neither NO production nor NK cell activation is critical for the resistance to P. berghei XAT infection and that IFN-γ plays an important role in the elimination of malarial parasites, possibly by the enhancement of phagocytic activity of macrophages.

γδ T cells modulate humoral immunity against Plasmodium berghei infection

“…Wild-type and TCR-d KO mice were infected with PbXAT. On days 14,16,18,20,22 and 24 post-infection (p.i. ), serum was taken from the PbXAT-infected WT mice.…”

“…Inhibition of IFN-c signalling by gene knockout (KO) or injection of neutralizing anti-IFN-c antibody led to worsening of the parasitaemia, resulting in loss of fluctuation of the parasitaemia. 9,22 Interferon-c activates phagocytosis by macrophages and monocytes. Therefore, the fluctuations in the parasitaemia of bloodstage PbXAT parasites are strongly related to IFN-c.…”

Expression of inducible nitric oxide synthase (iNOS) mRNA in target organs of lethal and non‐lethal strains of murine malaria

“…The data presented confirm and extend published results for NO and other RNI (23), and show iNOS mRNA expression is altered during these murine malarias. These observations indicate that increased iNOS, particularly in the spleen, contributes to the control of malaria, although its presence may not be essential (36,37,46). However, RNI can cause adverse as well as beneficial effects and other experimental approaches, especially pharmacological studies, are required to determine the benefits and risks associated with changes in iNOS during malaria.…”

IL‐12 p80‐dependent macrophage recruitment primes the host for increased survival following a lethal respiratory viral infection

“…42,43 These susceptibility differences may again be explained by systemic compared with local transgene expression or the differential requirement of IFN-c for host survival. IFN-c production is required for survival of P. berghei and L. major infections, and IFN-c expression was decreased in SAP-IL-12 p40 transgenic mice, [42][43][44][45][46] whereas we have shown that mortality from a Sendai viral infection is independent of IFN-c production. 3 Lastly, overexpression of IL-12 p40 using the keratinocyte-specific (K14) promoter resulted in the spontaneous accumulation of immune cells (macrophages, lymphocytes, eosinophils, mast cells and neutrophils) in the skin and the development of an inflammatory skin disease.…”