Gene-specific sex effects on eosinophil infiltration in leishmaniasis.

Martina Slapničková,Tatyana Kobets,Matyáš Šíma,Marie Čepičková,Milena Svobodová,Marie Lipoldová,Valeriya Volkova,Peter Demant

doi:10.1186/s13293-016-0117-3

Abstract

BackgroundSex influences susceptibility to many infectious diseases, including some manifestations of leishmaniasis. The disease is caused by parasites that enter to the skin and can spread to the lymph nodes, spleen, liver, bone marrow, and sometimes lungs. Parasites induce host defenses including cell infiltration, leading to protective or ineffective inflammation. These responses are often influenced by host genotype and sex. We analyzed the role of sex in the impact of specific gene loci on eosinophil infiltration and its functional relevance.MethodsWe studied the genetic control of infiltration of eosinophils into the inguinal lymph nodes after 8 weeks of Leishmania major infection using mouse strains BALB/c, STS, and recombinant congenic strains CcS-1,-3,-4,-5,-7,-9,-11,-12,-15,-16,-18, and -20, each of which contains a different random set of 12.5% genes from the parental “donor” strain STS and 87.5% genes from the “background” strain BALB/c. Numbers of eosinophils were counted in hematoxylin-eosin-stained sections of the inguinal lymph nodes under a light microscope. Parasite load was determined using PCR-ELISA.ResultsThe lymph nodes of resistant STS and susceptible BALB/c mice contained very low and intermediate numbers of eosinophils, respectively. Unexpectedly, eosinophil infiltration in strain CcS-9 exceeded that in BALB/c and STS and was higher in males than in females. We searched for genes controlling high eosinophil infiltration in CcS-9 mice by linkage analysis in F2 hybrids between BALB/c and CcS-9 and detected four loci controlling eosinophil numbers. Lmr14 (chromosome 2) and Lmr25 (chromosome 5) operate independently from other genes (main effects). Lmr14 functions only in males, the effect of Lmr25 is sex independent. Lmr15 (chromosome 11) and Lmr26 (chromosome 9) operate in cooperation (non-additive interaction) with each other. This interaction was significant in males only, but sex-marker interaction was not significant. Eosinophil infiltration was positively correlated with parasite load in lymph nodes of F2 hybrids in males, but not in females.ConclusionsWe demonstrated a strong influence of sex on numbers of eosinophils in the lymph nodes after L. major infection and present the first identification of sex-dependent autosomal loci controlling eosinophilic infiltration. The positive correlation between eosinophil infiltration and parasite load in males suggests that this sex-dependent eosinophilic infiltration reflects ineffective inflammation.

Highlights

Sex influences susceptibility to many infectious diseases, including some manifestations of leishmaniasis
Infiltration of eosinophils into the inguinal lymph nodes in parental strains BALB/c and STS and selected RC strains We infected with L. major both females and males of the strains BALB/c, STS, and RC strains CcS-1, CcS-3, CcS-4, CcS-5, CcS-7, CcS-9, CcS-11, CcS-12, CcS-15, CcS-16, CcS-18, and CcS-20 and used semi-quantitative scoring system to assess eosinophil infiltration (Table 1)
The lack of positive correlation between eosinophil infiltration and parasite load in Lmr14 heterozygotes (CS) may reflect a more effective inflammation process, perhaps facilitated by other phenotypic effects of Lmr14 that include circulating levels of IFNγ, TNF, IgE, and IL12 [91] and possibly other as yet undetected regulatory effects. This possibility has to be tested in future experiments. This is the first demonstration of genetic loci and sex influence controlling infiltration of eosinophils into the lymph nodes and its relationship with parasite load

Summary

Introduction

Sex influences susceptibility to many infectious diseases, including some manifestations of leishmaniasis. Parasites induce host defenses including cell infiltration, leading to protective or ineffective inflammation These responses are often influenced by host genotype and sex. The metastatic spread of the infection to the spleen and liver results in visceral leishmaniasis These are the major sites of visceral disease, parasites can enter other organs, such as the bone marrow, lymph nodes, and lungs (reviewed in [5]). Presence of parasites in organs usually induces inflammation through cascade of signals that leads to recruitment of inflammatory cells, such as neutrophils, macrophages, eosinophils, and dendritic cells. These innate immune cells might phagocytose parasites and/or produce cytokines and chemokines that activate both innate and adaptive immune responses. Resulting responses can be protective and eliminate parasites, or ineffective and lead to chronic inflammation [7]

Methods

Results

Discussion

Conclusion