Vaccine and Infectious Disease Organization-International Vaccine Centre, Saskatoon, Saskatchewan, Canada.
Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Infect Immun. 2021 Mar 17;89(4). doi: 10.1128/IAI.00810-20.
Nontyphoidal (NTS) strains are associated with gastroenteritis worldwide but are also the leading cause of bacterial bloodstream infections in sub-Saharan Africa. The invasive NTS (iNTS) strains that cause bloodstream infections differ from standard gastroenteritis-causing strains by >700 single-nucleotide polymorphisms (SNPs). These SNPs are known to alter metabolic pathways and biofilm formation and to contribute to serum resistance and are thought to signify iNTS strains becoming human adapted, similar to typhoid fever-causing strains. Identifying SNPs that contribute to invasion or increased virulence has been more elusive. In this study, we identified a SNP in the cache 1 signaling domain of diguanylate cyclase STM1987 in the invasive serovar Typhimurium type strain D23580. This SNP was conserved in 118 other iNTS strains analyzed and was comparatively absent in global Typhimurium isolates associated with gastroenteritis. STM1987 catalyzes the formation of bis-(3',5')-cyclic dimeric GMP (c-di-GMP) and is proposed to stimulate production of cellulose independent of the master biofilm regulator CsgD. We show that the amino acid change in STM1987 leads to a 10-fold drop in cellulose production and increased fitness in a mouse model of acute infection. Reduced cellulose production due to the SNP led to enhanced survival in both murine and human macrophage cell lines. In contrast, loss of CsgD-dependent cellulose production did not lead to any measurable change in fitness. We hypothesize that the SNP in represents a pathoadaptive mutation for iNTS strains.
非伤寒型（NTS）菌株与世界各地的胃肠炎有关，但也是撒哈拉以南非洲细菌性血流感染的主要原因。引起血流感染的侵袭性 NTS（iNTS）菌株与引起标准胃肠炎的菌株有超过 700 个单核苷酸多态性（SNPs）的差异。这些 SNPs 已知会改变代谢途径和生物膜形成，并有助于血清抗性，被认为标志着 iNTS 菌株适应人类，类似于引起伤寒的菌株。确定导致侵袭或增加毒力的 SNPs 一直更加难以捉摸。在这项研究中，我们在侵袭性血清型鼠伤寒菌 D23580 的环二鸟苷酸（c-di-GMP）合成酶 STM1987 的 cache 1 信号域中发现了一个 SNP。该 SNP 在分析的 118 种其他 iNTS 菌株中保守，而在与胃肠炎相关的全球鼠伤寒菌分离株中则相对不存在。STM1987 催化双-(3',5')-环二鸟苷酸（c-di-GMP）的形成，并被提议刺激纤维素的产生，而不依赖于主生物膜调节剂 CsgD。我们表明，STM1987 中的氨基酸变化导致纤维素产量下降 10 倍，并在急性感染的小鼠模型中提高了适应性。由于 SNP 导致纤维素产量减少，从而增强了在鼠和人巨噬细胞系中的存活能力。相比之下，CsgD 依赖性纤维素产生的丧失并没有导致适应性的任何可衡量的变化。我们假设 SNP 代表 iNTS 菌株的病理适应突变。
