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Gene-specific sex effects on eosinophil infiltration in leishmaniasis

View Article: PubMed Central - PubMed

ABSTRACT

Background: Sex 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.

Methods: We 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.

Results: The 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.

Conclusions: We 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.

No MeSH data available.


Eosinophils in hematoxylin-eosin-stained inguinal lymph node sections of L. major-infected female and male mice. a BALB/c female, b BALB/c male, c STS female, d STS male, e CcS-9 female, and f CcS-9 male with detail of eosinophils. Arrows show positions of eosinophils
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Fig1: Eosinophils in hematoxylin-eosin-stained inguinal lymph node sections of L. major-infected female and male mice. a BALB/c female, b BALB/c male, c STS female, d STS male, e CcS-9 female, and f CcS-9 male with detail of eosinophils. Arrows show positions of eosinophils

Mentions: These studies showed mild and no infiltration into the lymph nodes of parental strains BALB/c (Fig. 1a, b) and STS (Fig. 1c, d), respectively. Strains CcS-9 (P = 0.00020) (Fig. 1e, f) and CcS-12 (P = 0.0024) exhibit significantly higher eosinophil infiltration in their lymph nodes than the background parental strain BALB/c. BALB/c and CcS-9 males presented higher eosinophil infiltration than females of these strains P = 0.0089 and P = 0.016, respectively. 80% of examined CcS-9 males in comparison with 26.67% of CcS-9 females contained infiltrating eosinophils, 50% of males having 7 and more eosinophils in their lymph nodes (Table 1). Sex difference in strains CcS-7,-11, and -18 was not significant. Strain CcS-9 with the highest eosinophil infiltration (Table 1) was selected for further genetic studies.Fig. 1


Gene-specific sex effects on eosinophil infiltration in leishmaniasis
Eosinophils in hematoxylin-eosin-stained inguinal lymph node sections of L. major-infected female and male mice. a BALB/c female, b BALB/c male, c STS female, d STS male, e CcS-9 female, and f CcS-9 male with detail of eosinophils. Arrows show positions of eosinophils
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5120444&req=5

Fig1: Eosinophils in hematoxylin-eosin-stained inguinal lymph node sections of L. major-infected female and male mice. a BALB/c female, b BALB/c male, c STS female, d STS male, e CcS-9 female, and f CcS-9 male with detail of eosinophils. Arrows show positions of eosinophils
Mentions: These studies showed mild and no infiltration into the lymph nodes of parental strains BALB/c (Fig. 1a, b) and STS (Fig. 1c, d), respectively. Strains CcS-9 (P = 0.00020) (Fig. 1e, f) and CcS-12 (P = 0.0024) exhibit significantly higher eosinophil infiltration in their lymph nodes than the background parental strain BALB/c. BALB/c and CcS-9 males presented higher eosinophil infiltration than females of these strains P = 0.0089 and P = 0.016, respectively. 80% of examined CcS-9 males in comparison with 26.67% of CcS-9 females contained infiltrating eosinophils, 50% of males having 7 and more eosinophils in their lymph nodes (Table 1). Sex difference in strains CcS-7,-11, and -18 was not significant. Strain CcS-9 with the highest eosinophil infiltration (Table 1) was selected for further genetic studies.Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: Sex 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.

Methods: We 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.

Results: The 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.

Conclusions: We 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.

No MeSH data available.