Outcome of primary lethal and nonlethal Plasmodium yoelii malaria infection in BALB/c and IFN-γ receptor-deficient mice following chloroquine treatment

Abstract

IFN-γ receptor-deficient (IFN-γR(-/-)) mice and control wild-type (WT) mice, with or without chloroquine (CQ) treatment, were infected intraperitoneally with Plasmodium yoelii 17XL (lethal) and P. yoelii 17XNL (nonlethal), and then mouse survival, parasitemia, and antibody production were investigated during the course of infection. Without CQ treatment, both IFN-γR(-/-) and WT mice were susceptible to infection showing 100 % mortality after infection with 1 × 10(5) P. yoelii 17XL-parasitized erythrocytes. The P. yoelii 17XL-infected WT mice could survive by CQ treatment at a dose of 20 mg/kg for 3 days from day 3 postinfection (pi). Malaria parasites in their bloodstream could not be detected in the surviving mice after day 13 pi. CQ treatment, however, could not rescue IFN-γR(-/-) mice infected with P. yoelii 17XL. Next, we examined the production of the parasite-specific antibodies in P. yoelii 17XL-infected, CQ-treated mice. Although the production of malaria-specific IgG1, IgG2a, IgG2b, and IgG3 antibodies was observed on days 14 and 28 pi in WT mouse sera, only IgG1 was detected on day 28 pi in IFN-γR(-/-) mouse sera. On the other hand, in the nonlethal P. yoelii 17XNL infection, WT mice could control a primary infection with 1 × 10(5) parasitized erythrocytes. Although IFN-γR(-/-) mice could not control and died with increasing parasitemia, the mice could survive by CQ treatment. Both WT and IFN-γR(-/-) mice with and without medication, which survived from P. yoelii 17XNL infection, showed the variable levels of malaria-specific IgG1, IgG2a, IgG2b, and IgG3 antibodies during the course of infection. The present data indicate that the IFN-γ receptors are needed to control the infection and parasite-specific IgG2a antibody plays an essential role in recovery from the infection of erythrocytic stages of P. yoelii 17XL or P. yoelii 17XNL parasite.

Contributions of IFN-γ and granulysin to the clearance of Plasmodium yoelii blood stage

“…We confirm the results from Okada et al (2015) showing that reticulocytosis is decreased in P. yoelii-infected IFN-γ KO mice (S5C Fig). However, in sharp contrast with Okada et al (2015) findings, we report that IFN-γ KO mice infected with P. yoelii had increased parasitemia and succumbed to infection with a non-lethal strain of P. yoelii [33,34]. Importantly, Retics and iRetics from IFN-γ KO mice infected with P. yoelii did not express MHC-I.…”

Mechanism of splenic cell death and host mortality in a Plasmodium yoelii malaria model

“…IFN-γ produced by activated T cells has been shown to be critical for immune protection in various studies 22 , 32 , 56 – 61 . Mice deficient in IFN-γ signaling have a delayed parasitemia resolution 62 , 63 , and IFN-γ and IFN-γ-induced chemokines are required for mobilization of myeloid progenitors to the spleen during P. chabaudi infection 49 . Elevated levels of IFN-γ are also correlated with natural resistance to P. falciparum infection in the Malian Fulani population 56 .…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…235,236 In malaria, a critical 3-day time course is needed to mount an immune response before a 50 mg/kg dose of CQ can be added to the treatment regimen. In the case of malaria, an effective T helper type 1 (Th1) -dominated immune response requires TLR4, TLR9, interferon-c (IFN-c), and immunoglobulins IgG2a, IgG2b, and IgG3.…”

“…In the case of malaria, an effective T helper type 1 (Th1) -dominated immune response requires TLR4, TLR9, interferon-c (IFN-c), and immunoglobulins IgG2a, IgG2b, and IgG3. 235,236 In malaria, a critical 3-day time course is needed to mount an immune response before a 50 mg/kg dose of CQ can be added to the treatment regimen. 237 The capacity of CQ to protect tumors from the mammalian immune system is evident by adding CQ to curcumin in immunocompetent mice.…”