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Toll-like receptors and cytokines in immune responses to persistent mycobacterial and Salmonella infections

Balaram P, Kien PK, Ismail A

Int J Med Microbiol, 2009 Mar;299(3):177-85.
PMID: 18845475 DOI: 10.1016/j.ijmm.2008.08.004

Bacterial persistence is of major concern worldwide in the control of a number of bacterial infections. The carriers who are asymptomatic act as reservoirs of the bacteria. Knowledge of the host response, of the persistence process, and of the potential of biological mediators as diagnostic markers is essential towards development of prophylactic and treatment modalities for these diseases. Immune mechanisms related to recognition and elimination of the bacteria play pivotal roles in the control of bacterial infections. The majority of the studies on bacterial infections detail the immune mechanisms in the active phase of infection, and reports on the immune status in carriers are scanty. The present review describes the role of recognition molecules (TLRs) and the immune mediators (cytokines) in bacterial persistence. It appears that the TLR-mediated induction of cytokine profiles differs in active infection and bacterial persistence, with an active Th1 response being beneficial for the clearance of a high load of bacteria and at the same time conducive for the persistence of low bacterial load. Immunomodulation aiming at stimulation of the immune responses should be carried out with care as it could give rise to a carrier state in individuals with low load of the bacteria.
TolC facilitates the intracellular survival and immunomodulation of Salmonella Typhi in human host cells

Hussain A, Ong EBB, Balaram P, Ismail A, Kien PK

Virulence, 2024 Dec;15(1):2395831.
PMID: 39185619 DOI: 10.1080/21505594.2024.2395831

Salmonella enterica serovar Typhi (S. Typhi) causes typhoid fever, a systemic infection that affects millions of people worldwide. S. Typhi can invade and survive within host cells, such as intestinal epithelial cells and macrophages, by modulating their immune responses. However, the immunomodulatory capability of S. Typhi in relation to TolC-facilitated efflux pump function remains unclear. The role of TolC, an outer membrane protein that facilitates efflux pump function, in the invasion and immunomodulation of S. Typhi, was studied in human intestinal epithelial cells and macrophages. The tolC deletion mutant of S. Typhi was compared with the wild-type and its complemented strain in terms of their ability to invade epithelial cells, survive and induce cytotoxicity in macrophages, and elicit proinflammatory cytokine production in macrophages. The tolC mutant, which has a defective outer membrane, was impaired in invading epithelial cells compared to the wild-type strain, but the intracellular presence of the tolC mutant exhibited greater cytotoxicity and induced higher levels of proinflammatory cytokines (IL-1β and IL-8) in macrophages compared to the wild-type strain. These effects were reversed by complementing the tolC mutant with a functional tolC gene. Our results suggest that TolC plays a role in S. Typhi to efficiently invade epithelial cells and suppress host immune responses during infection. TolC may be a potential target for the development of novel therapeutics against typhoid fever.
Fulltext Deletion of Salmonella enterica serovar Typhi tolC reduces bacterial adhesion and invasion toward host cells

Hussain A, Ong EBB, Balaram P, Ismail A, Kien PK

Front Microbiol, 2023;14:1301478.
PMID: 38029101 DOI: 10.3389/fmicb.2023.1301478

BACKGROUND: S. Typhi is a Gram-negative bacterium that causes typhoid fever in humans. Its virulence depends on the TolC outer membrane pump, which expels toxic compounds and antibiotics. However, the role of TolC in the host cell adhesion and invasion by S. Typhi is unclear.
OBJECTIVE: We aimed to investigate how deleting the tolC affects the adhesion and invasion of HT-29 epithelial and THP-1 macrophage cells by S. Typhi in vitro.
METHODS: We compared the adhesion and invasion rates of the wild-type and the tolC mutant strains of S. Typhi using in vitro adhesion and invasion assays. We also measured the expression levels of SPI-1 genes (invF, sipA, sipC, and sipD) using quantitative PCR.
RESULTS: We found that the tolC mutant showed a significant reduction in adhesion and invasion compared to the wild-type strain in both cell types. We also observed that the expression of SPI-1 genes was downregulated in the tolC mutant.
DISCUSSION: Our results suggest that TolC modulates the expression of SPI-1 genes and facilitates the adhesion and invasion of host cells by S. Typhi. Our study provides new insights into the molecular mechanisms of S. Typhi pathogenesis and antibiotic resistance. However, our study is limited by the use of in vitro models and does not reflect the complex interactions between S. Typhi and host cells in vivo.

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