Testosterone and other gonadal factor(s) restrict the efficacy of genes controlling resistance to Plasmodium chabaudi malaria

Wunderlich, Frank; Marinovski, Predrag; Benten, W. Peter M.; Schmitt-Wrede, Hans-Peter; Mossmann, Horst

doi:10.1111/j.1365-3024.1991.tb00289.x

Cited by 75 publications

(64 citation statements)

References 27 publications

(3 reference statements)

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“…Among humans, although the incidence of infection is often similar between the sexes (see references 51 and 52), sex differences in the intensity of infection are reported in which men have higher parasitemia than women (23, 32, 52). The observation that P. falciparum (i.e., a human malaria parasite) density increases at puberty in men, but not in women, suggests that circulating sex steroids may influence this outcome (23).Studies of rodent malarias have confirmed that males are more likely to die after blood-stage malaria infection than are females (2,3,(54)(55)(56) …”

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Involvement of Gonadal Steroids and Gamma Interferon in Sex Differences in Response to Blood-Stage Malaria Infection

et al. 2006

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To examine the hormonal and immunological mechanisms that mediate sex differences in susceptibility to malaria infection, intact and gonadectomized (gdx) C57BL/6 mice were inoculated with Plasmodium chabaudi AS-infected erythrocytes, and the responses to infection were monitored. In addition to reduced mortality, intact females recovered from infection-induced weigh loss and anemia faster than intact males. Expression microarrays and real-time reverse transcription-PCR revealed that gonadally intact females exhibited higher expression of interleukin-10 (IL-10), IL-15R␣, IL-12R␤, Gadd45␥, gamma interferon (IFN-␥), CCL3, CXCL10, CCR5, and several IFN-inducible genes in white blood cells and produced more IFN-␥ than did intact males and gdx females, with these differences being most pronounced during peak parasitemia. Intact females also had higher anti-P. chabaudi immunoglobulin G (IgG) and IgG1 responses than either intact males or gdx females. To further examine the effector mechanisms mediating sex differences in response to P. chabaudi infection, responses to infection were compared among male and female wild-type (WT), T-cell-deficient (TCR␤␦ ؊/؊ ), B-cell-deficient (MT), combined T-and B-cell-deficient (RAG1), and IFN-␥ knockout (IFN-␥ ؊/؊ ) mice. Males were 3.5 times more likely to die from malaria infection than females, with these differences being most pronounced among TCR␤␦ ؊/؊ , MT, and RAG1 mice. Male mice also exhibited more severe weight loss, anemia, and hypothermia, and higher peak parasitemia than females during infection, with WT, RAG1, TCR␤␦ ؊/؊ , and MT mice exhibiting the most pronounced sexual dimorphism. The absence of IFN-␥ reduced the sex difference in mortality and was more detrimental to females than males. These data suggest that differential transcription and translation of IFN-␥, that is influenced by estrogens, may mediate sex differences in response to malaria.Males are more susceptible to many protozoan infections than females and field and laboratory studies link increased susceptibility to infection with circulating steroid hormones (17,18,39). One genus of protozoan parasites that causes a pronounced sexual dimorphism in vertebrate hosts is Plasmodium. Among humans, although the incidence of infection is often similar between the sexes (see references 51 and 52), sex differences in the intensity of infection are reported in which men have higher parasitemia than women (23, 32, 52). The observation that P. falciparum (i.e., a human malaria parasite) density increases at puberty in men, but not in women, suggests that circulating sex steroids may influence this outcome (23).Studies of rodent malarias have confirmed that males are more likely to die after blood-stage malaria infection than are females (2,3,(54)(55)(56)

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“…Studies of rodent malarias have confirmed that males are more likely to die after blood-stage malaria infection than are females (2,3,(54)(55)(56)…”

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confidence: 99%

Involvement of Gonadal Steroids and Gamma Interferon in Sex Differences in Response to Blood-Stage Malaria Infection

et al. 2006

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“…28 This has been shown to be dependent on testosterone, as male castration improves infection outcome and testosterone administration to females increases susceptibility. [29][30][31] These results suggest that the strong malaria-protective effect of PK deficiency is modified by other genetic factors in AcB62, and that susceptibility in this strain is dominant.…”

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Mapping of Char10, a novel malaria susceptibility locus on mouse chromosome 9

Min‐Oo¹,

Willemetz²,

Tam³

et al. 2009

Genes Immun

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Resistance to blood-stage malaria in AcB55 and AcB61 is caused by a loss of function mutation in pyruvate kinase (Pklr I90N ). Likewise, pyruvate kinase (PK) deficiency in humans is protective against Plasmodium replication in vitro. We identified a third AcB strain, AcB62 that also carries the Pklr I90N mutation. However, AcB62 mice were susceptible to P.chabaudi infection and showed high levels of parasite replication (54-62% peak parasitemia). AcB62 mice showed the hallmarks of PK deficiencyassociated anemia similar to AcB55/61 with reticulocytosis, splenic red pulp expansion, tissue iron overload, and increased expression of iron metabolism proteins. This suggests that malaria susceptibility in AcB62 is not because of absence of PK deficiency-associated pathophysiology. To map novel genetic factors affecting malaria susceptibility in AcB62, we generated an informative F2 population using AcB62 (Pklr I90N ) and CBA-Pk slc (Pklr G338D ) as progenitors and identified a novel locus on chromosome 9 (Char10; LOD ¼ 7.24) that controls peak parasitemia. A weaker linkage to the Pklr region of chromosome 3 (LOD ¼ 3.7) was also detected, a finding that may reflect the segregation of the two defective Pklr alleles. AcB62 alleles at both loci are associated with higher peak parasitemia. These results identify Char10 as a novel locus modulating severity of malaria in the context of PK deficiency.

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“…In the experimental mouse malaria Plasmodium chabaudi, testosterone has been shown to induce a lethal outcome of otherwise self-healing infections (Wunderlich et al 1988(Wunderlich et al , 1991. Remarkably, this testosterone-induced conversion from resistance to susceptibility becomes somehow imprinted in female mice, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…Female C57BL/6 mice were treated with testosterone or vehicle twice a week for 3 weeks. The testosteronetreated mice were previously shown to loose their capability of self-healing malaria infections when challenged with 10 6 P. chabaudi-infected erythrocytes (Wunderlich et al 1988(Wunderlich et al , 1991. The treatment was discontinued for 12 weeks, before the mice were challenged with P. chabaudi malaria reaching peak parasitemia of w50% on day 8 p.i.…”

Section: Experimental Designmentioning

confidence: 99%

Testosterone-induced permanent changes of hepatic gene expression in female mice sustained during Plasmodium chabaudi malaria infection

Delić

Gailus

Vohr

et al. 2010

Journal of Molecular Endocrinology

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Testosterone has been previously shown to induce persistent susceptibility to Plasmodium chabaudi malaria in otherwise resistant female C57BL/6 mice. Here, we investigate as to whether this conversion coincides with permanent changes of hepatic gene expression profiles. Female mice aged 10-12 weeks were treated with testosterone for 3 weeks; then, testosterone treatment was discontinued for 12 weeks before challenging with 10 6 P. chabaudi-infected erythrocytes.Hepatic gene expression was examined after 12 weeks of testosterone withdrawal and after subsequent infection with P. chabaudi at peak parasitemia, using Affymetrix microarrays with 22 690 probe sets representing 14 000 genes. The expression of 54 genes was found to be permanently changed by testosterone, which remained changed during malaria infection. Most genes were involved in liver metabolism: the female-prevalent genes Cyp2b9, Cyp2b13, Cyp3a41, Cyp3a44, Fmo3, Sult2a2, Sult3a1, and BC014805 were repressed, while the male-prevalent genes Cyp2d9, Cyp7b1, Cyp4a10, Ugt2b1, Ugt2b38, Hsd3b5, and Slco1a1 were upregulated. Genes encoding different nuclear receptors were not persistently changed. Moreover, testosterone induced persistent upregulation of genes involved in hepatocellular carcinoma such as Lama3 and Nox4, whereas genes involved in immune response such as Ifng and Igk-C were significantly decreased. Our data provide evidence that testosterone is able to induce specific and robust long-term changes of gene expression profiles in the female mouse liver. In particular, those changes, which presumably indicate masculinized liver metabolism and impaired immune response, may be critical for the testosterone-induced persistent susceptibility of mice to P. chabaudi malaria.

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Testosterone and other gonadal factor(s) restrict the efficacy of genes controlling resistance to Plasmodium chabaudi malaria

Cited by 75 publications

References 27 publications

Involvement of Gonadal Steroids and Gamma Interferon in Sex Differences in Response to Blood-Stage Malaria Infection

Involvement of Gonadal Steroids and Gamma Interferon in Sex Differences in Response to Blood-Stage Malaria Infection

Mapping of Char10, a novel malaria susceptibility locus on mouse chromosome 9

Testosterone-induced permanent changes of hepatic gene expression in female mice sustained during Plasmodium chabaudi malaria infection

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