Université Toulouse 3 Paul Sabatier, CNRS, ENFA, UMR5174 EDB (Laboratoire Évolution & Diversité Biologique), 118 route de Narbonne, F-31062, Toulouse, France.
CNRS, Université Paul Sabatier, UMR5174 EDB, F-31062, Toulouse, France.
BMC Biol. 2017 Dec 21;15(1):124. doi: 10.1186/s12915-017-0466-3.
Host sexual dimorphism is being increasingly recognized to generate strong differences in the outcome of infectious disease, but the mechanisms underlying immunological differences between males and females remain poorly characterized. Here, we used Drosophila melanogaster to assess and dissect sexual dimorphism in the innate response to systemic bacterial infection.
We demonstrated sexual dimorphism in susceptibility to infection by a broad spectrum of Gram-positive and Gram-negative bacteria. We found that both virgin and mated females are more susceptible than mated males to most, but not all, infections. We investigated in more detail the lower resistance of females to infection with Providencia rettgeri, a Gram-negative bacterium that naturally infects D. melanogaster. We found that females have a higher number of phagocytes than males and that ablation of hemocytes does not eliminate the dimorphism in resistance to P. rettgeri, so the observed dimorphism does not stem from differences in the cellular response. The Imd pathway is critical for the production of antimicrobial peptides in response to Gram-negative bacteria, but mutants for Imd signaling continued to exhibit dimorphism even though both sexes showed strongly reduced resistance. Instead, we found that the Toll pathway is responsible for the dimorphism in resistance. The Toll pathway is dimorphic in genome-wide constitutive gene expression and in induced response to infection. Toll signaling is dimorphic in both constitutive signaling and in induced activation in response to P. rettgeri infection. The dimorphism in pathway activation can be specifically attributed to Persephone-mediated immune stimulation, by which the Toll pathway is triggered in response to pathogen-derived virulence factors. We additionally found that, in absence of Toll signaling, males become more susceptible than females to the Gram-positive Enterococcus faecalis. This reversal in susceptibility between male and female Toll pathway mutants compared to wildtype hosts highlights the key role of the Toll pathway in D. melanogaster sexual dimorphism in resistance to infection.
Altogether, our data demonstrate that Toll pathway activity differs between male and female D. melanogaster in response to bacterial infection, thus identifying innate immune signaling as a determinant of sexual immune dimorphism.
宿主的性别二态性正逐渐被认为会对传染病的转归产生巨大差异，但男性和女性之间免疫差异的潜在机制仍知之甚少。在这里，我们使用黑腹果蝇来评估和剖析系统性细菌感染的先天反应中的性别二态性。
我们证明了对广谱革兰氏阳性和革兰氏阴性菌感染的易感性存在性别二态性。我们发现，无论是处女还是交配后的雌性，对大多数（但不是所有）感染都比交配后的雄性更容易感染。我们更详细地研究了雌性对自然感染黑腹果蝇的革兰氏阴性菌普罗维登斯雷氏菌的抵抗力较低的原因。我们发现雌性的吞噬细胞数量多于雄性，并且去除血淋巴细胞并不能消除对 P. rettgeri 的抗性二态性，因此观察到的二态性并非源于细胞反应的差异。Imd 途径对于革兰氏阴性细菌产生抗菌肽至关重要，但 Imd 信号突变体即使两性的抵抗力都明显降低，仍继续表现出二态性。相反，我们发现 Toll 途径负责抗性的二态性。Toll 途径在全基因组组成性基因表达和对感染的诱导反应中存在二态性。Toll 信号在组成性信号和对 P. rettgeri 感染的诱导激活中都存在二态性。通路激活的二态性可以特异性归因于 Persephone 介导的免疫刺激，通过这种刺激，Toll 通路会被病原体来源的毒力因子触发。我们还发现，在没有 Toll 信号的情况下，雄性比雌性对革兰氏阳性粪肠球菌更易感染。与野生型宿主相比，雄性和雌性 Toll 途径突变体之间对感染的易感性的这种逆转突显了 Toll 途径在黑腹果蝇对感染的抗性性别二态性中的关键作用。
总之，我们的数据表明，Toll 途径在黑腹果蝇对细菌感染的反应中在两性之间存在活性差异，从而确定先天免疫信号作为性别免疫二态性的决定因素。
