Hamblin Meagan, Schade Ruth, Narasimhan Ramya, Monack Denise M
bioRxiv. 2023 Jun 7:2023.06.06.543980. doi: 10.1101/2023.06.06.543980.
serovar Typhi ( Typhi) is a human-restricted pathogen that replicates in macrophages. In this study, we investigated the roles of the Typhi Type 3 secretion systems (T3SSs) encoded on Pathogenicity Islands (SPI) -1 (T3SS-1) and -2 (T3SS-2) during human macrophage infection. We found that mutants of . Typhi deficient for both T3SSs were defective for intramacrophage replication as measured by flow cytometry, viable bacterial counts, and live time-lapse microscopy. T3SS-secreted proteins PipB2 and SifA contributed to Typhi replication and were translocated into the cytosol of human macrophages through both T3SS-1 and -2, demonstrating functional redundancy for these secretion systems. Importantly, an . Typhi mutant strain that is deficient for both T3SS-1 and -2 was severely attenuated in the ability to colonize systemic tissues in a humanized mouse model of typhoid fever. Overall, this study establishes a critical role for Typhi T3SSs during its replication within human macrophages and during systemic infection of humanized mice.
serovar Typhi is a human-restricted pathogen that causes typhoid fever. Understanding the key virulence mechanisms that facilitate Typhi replication in human phagocytes will enable rational vaccine and antibiotic development to limit spread of this pathogen. While Typhimurium replication in murine models has been studied extensively, there is limited information available about Typhi replication in human macrophages, some of which directly conflicts with findings from Typhimurium murine models. This study establishes that both of Typhi's two Type 3 Secretion Systems (T3SS-1 and -2) contribute to intramacrophage replication and virulence.
伤寒杆菌（Typhi）是一种仅限于人类的病原体，在巨噬细胞中复制。在本研究中，我们调查了位于致病岛（SPI）-1（T3SS-1）和-2（T3SS-2）上编码的伤寒杆菌III型分泌系统（T3SSs）在人类巨噬细胞感染过程中的作用。我们发现，通过流式细胞术、活菌计数和实时延时显微镜观察，两种T3SS均缺陷的伤寒杆菌突变体在巨噬细胞内复制存在缺陷。T3SS分泌的蛋白PipB2和SifA有助于伤寒杆菌的复制，并通过T3SS-1和-2转运到人类巨噬细胞的细胞质中，证明了这些分泌系统的功能冗余。重要的是，在伤寒热的人源化小鼠模型中，一种T3SS-1和-2均缺陷的伤寒杆菌突变株在定殖于全身组织的能力上严重减弱。总体而言，本研究确立了伤寒杆菌T3SS在其于人类巨噬细胞内复制以及人源化小鼠全身感染过程中的关键作用。
伤寒杆菌是一种仅限于人类的病原体，可引起伤寒热。了解促进伤寒杆菌在人类吞噬细胞中复制的关键毒力机制，将有助于合理开发疫苗和抗生素，以限制这种病原体的传播。虽然鼠伤寒杆菌在鼠模型中的复制已得到广泛研究，但关于伤寒杆菌在人类巨噬细胞中复制的信息有限，其中一些信息与鼠伤寒杆菌鼠模型的研究结果直接冲突。本研究证实，伤寒杆菌的两种III型分泌系统（T3SS-1和-2）均有助于巨噬细胞内复制和毒力。
