At Home with Hostility

By Thomas Ruby and Denise M. Monack At Home with Hostility How do pathogenic bacteria evade mammalian immune surveillance to establish persistent infection? Tuberculosis infection Scott Camazine / Photo Researchers, Inc. Long-term bacterial infections pose several fundamental biological questions: How metabolically active are bacteria during a persistent infection? Are they dividing, or in a state of quiescence? And how do these bacteria evade the immune system

Thomas Ruby and Denise M. Monack
Dec 1, 2010

At Home with Hostility

How do pathogenic bacteria evade mammalian immune surveillance to establish persistent infection?

Tuberculosis infection
Scott Camazine / Photo Researchers, Inc.

Long-term bacterial infections pose several fundamental biological questions: How metabolically active are bacteria during a persistent infection? Are they dividing, or in a state of quiescence? And how do these bacteria evade the immune system for so long?

Acute infections by pathogenic bacteria cause a dramatic activation of the innate and adaptive immune responses. If the pathogen survives initial contact with the host’s innate immune system (and the host is not killed), the infection is usually cleared by the host’s adaptive immune system. However, some bacterial pathogens maintain infections for the lifetime of their mammalian hosts, even in the presence of a robust immune response.

Most of what we’ve learned about persistent infections comes from the study of several well-known illnesses. For example, Helicobacter pylori, the...

We are only now beginning to understand the bacterial and host factors involved in the host–pathogen interaction during persistent infection, and these new discoveries are likely to provide new and exciting directions for research in the fields of microbial pathogenesis and immunology.

Making a better replicative niche

H. pylori is uniquely adapted to colonize the hostile environment of the human stomach. More virulent strains of H. pylori inject virulence factors into gastric epithelial cells, a step that is associated with the development of stomach cancer. These factors provide an advantage to the invading bacterium because they disrupt epithelial cell polarity. This allows bacteria to attach and grow on the apical surface of epithelial cells, where it may be easier for them to acquire the nutrients necessary for survival.2

Salmonella has developed its own mechanisms for colonizing a host and replicating despite the presence of immune cells. Most of the information on Salmonella immune-evasion mechanisms has come from a mouse model of persistent Salmonella Typhimurium infection. Salmonella Typhimurium colonizes the mesenteric lymph nodes of these mice—a gathering place for immune cells—and is occasionally found in the gallbladder, liver, and spleen. The bacterium achieves this by secreting the protein SseI, which promotes long-term infection by subverting immune activation. The protein interferes with the migration of infected cells to lymphoid tissues by specifically binding to the cell-migration regulator IQGAP.3 This prevents normal dendritic-cell migration, limiting presentation of Salmonella antigens and naïve T-cell priming, and thereby inhibiting adaptive immunity.4

Subverting the host

Analyzing the role of host immune factors in chronic Salmonella infection has shed light on the mechanisms that allow for persistent bacterial growth. For example, regulatory T cells, which control the balance between immune-cell activation and suppression, can dictate the course of persistent Salmonella infection by suppressing the adaptive immune response. Leucocytes can also play a role in tuberculosis, where progression from a latent, subclinical infection to active disease is controlled by foamy macrophages within a granuloma (a spherical mass of immune cells that forms around a pathogen that can’t be cleared). The foamy macrophage appears to be a key participant in both sustaining bacteria and contributing to the tissue pathology that leads to the release of infectious bacilli. The normally beneficial macrophages become pathologic in this situation through pathogen-initiated dysregulation of lipid synthesis.5

Studying mechanisms of bacterial persistence is made more difficult by the presence of native (nonpathogenic) organisms, particularly in the human gut. The human gut microflora is important in regulating host inflammatory responses and preventing inappropriate (anti-self) immune responses. Interactions between gut microbiota and the immune system are under intense scrutiny because of their potential effects on persistent infections and, therefore, on the health of an individual. Recent studies have delved further into our understanding of this relationship by identifying host-specific bacteria responsible for directly modulating the gut immune response towards Salmonella.6,7 Further studies are now needed to evaluate the impact of the gut microbiota on the establishment of persistent systemic infections.

Faculty Member References:

1. R.A. Kingsley et al., “Epidemic multiple drug resistant Salmonella Typhimurium causing invasive disease in sub-Saharan Africa have a distinct genotype,” Genome Res, 19:2279-87, 2009. F1000 ID 2975958, Free F1000 Evaluation
2. S. Tan et al., “Helicobacter pylori usurps cell polarity to turn the cell surface into a replicative niche,” PLoS Pathog, 5:e1000407, 2009. F1000 ID 1161349, Free F1000 Evaluation
3. T.D. Lawley et al., “Genome-wide screen for Salmonella genes required for long-term systemic infection of the mouse,” PLoS Pathog, 2:e11, 2006. F1000 ID 1031418, Free F1000 Evaluation
4. L.M. McLaughlin et al., “The Salmonella SPI2 effector SseI mediates long-term systemic infection by modulating host cell migration,” PLoS Pathog, 5: e1000671, 2009. F1000 ID 1355962, Free F1000 Evaluation
5. D.G. Russell et al., “Foamy macrophages and the progression of the human tuberculosis granuloma,” Nat Immunol, 10: 943-48, 2009.
6. V. Gaboriau-Routhiau et al., “The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses,” Immunity, 31:677-89, 2009. F1000 ID 1273956, Free F1000 Evaluation
7. D. Kelly et al., “Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA,” Nat Immunol, 5:104-12, 2004. F1000 ID 1002208, Free F1000 Evaluation

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