Pregnancy impairs the innate immune resistance to salmonella typhimurium leading to rapid fatal infection
Pregnancy impairs the innate immune resistance to salmonella typhimurium leading to rapid fatal infection
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DOI：
10.4049/jimmunol.179.9.6088
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发表时间：
2007-11-01
影响因子：
4.4
通讯作者：
Krishnan, Laksluni
中科院分区：
文献类型：
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作者：
Pejcic-Karapetrovic, Branka;Gurnani, Komal;Krishnan, Laksluni
由肠道沙门氏菌引起的伤寒和胃肠炎在全球范围内不断增加。怀孕会带来很高的风险，但目前还不清楚母体对感染的免疫力是如何改变的。在小鼠中，敏感菌株死于S。肠血清型鼠伤寒沙门氏菌（ST）感染，而抗性小鼠（129 × 1/Svj）发展为慢性感染。我们发现，在正常耐药的129 X1/SvJ小鼠中，妊娠期间的强毒ST感染诱发了类似于100%的胎儿丢失，令人惊讶的是>60%的宿主死亡率，中位生存期为6天。妊娠小鼠脾脏细菌负荷高出1000倍。这与先天免疫细胞（树突细胞、中性粒细胞和NK细胞）的脾脏募集/扩增减少相关。特别是，脾扩张和NK细胞感染后的激活，在非妊娠小鼠中看到的是缺乏在怀孕。最值得注意的是，妊娠感染小鼠血清IL-12的产生减少，IL-6水平增加。此外，妊娠感染小鼠的子宫胎盘组织中IL-6 mRNA的表达相对于未感染的胎盘表现出相似的40倍的增加，而IL-12 p4 O没有增加。体内阻断IL-6可显著降低妊娠小鼠脾脏细菌负荷，但未能预防胎儿丢失。胎儿死亡与感染的速度有关;到14小时，ST在胎盘中扩展到>10（5），并已到达胎儿。因此，ST的优先胎盘扩增明显改变了对IL-6和远离IL-12的炎症反应，减少了脾脏先天免疫细胞的募集/激活。因此，高毒力病原体可能利用胎盘侵入来改变宿主对感染的系统抵抗力。
Typhoid fever and gastroenteritis caused by Salmonella enterica species are increasing globally. Pregnancy poses a high risk, but it is unclear how maternal immunity to infection is altered. In mice, susceptible strains die of S. enterica serovar typhimurium (ST) infection within 7 days whereas resistant mice (129 X 1/Svj) develop a chronic infection. We found that virulent ST infection during pregnancy, in normally resistant 129X1/SvJ mice, evoked similar to 100% fetal loss and surprisingly >60% host fatality, with a median survival of 6 days. Splenic bacterial load was 1000-fold higher in pregnant mice. This correlated to a diminished splenic recruitment/expansion of innate immune cells: dendritic cells, neutrophils, and NK cells. In particular, the splenic expansion and activation of NK cells postinfection seen in nonpregnant mice was lacking in pregnancy. Most notably, pregnant-infected mice had decreased production of serum IL-12 and increased IL-6 levels. Moreover, uteroplacental tissue of pregnant-infected mice exhibited an similar to 40-fold increase in IL-6 mRNA expression relative to noninfected placenta, whereas IL-12p4O was not increased. In vivo blocking of IL-6 significantly reduced the splenic bacterial burden in pregnant mice yet failed to prevent fetal loss. Fetal demise correlated to the rapidity of infection; by 14 h, ST expanded to >10(5) in the placenta and had reached the fetus. Therefore, the preferential placental expansion of ST plausibly altered the inflammatory response toward IL-6 and away from IL-12, reducing the recruitment/activation of splenic innate immune cells. Thus,, highly virulent pathogens may use placental invasion to alter systemic host resistance to infection.