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  • Review Article
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Persistent bacterial infections: the interface of the pathogen and the host immune system

Nature Reviews Microbiology volume 2, pages 747–765 (2004)Cite this article

Key Points

  • Bacterial pathogens capable of persisting in human hosts for long periods of time fall into at least two classes.

  • One class is defined by a group of organisms that, after causing an initial disease state, are kept in check by an adaptive immune response for long periods of time, although sterilizing immunity is not achieved.

  • A second class of well-known bacterial pathogens are carried asymptomatically within most people among the commensal flora, but still possess the ability to cause life-threatening disease in seemingly immunocompetent individuals.

  • We focus on three bacterial pathogens from the first class that can persist in the human for long periods of time and are not considered to be part of the normal human flora. These are Mycobacterium spp., Salmonella spp, and Helicobacter pylori.

  • We discuss some of the strategies of these persistent bacteria. For example, some bacteria persist in a privileged niche, perhaps inside host cells. Mycobacterium spp. and Salmonella spp. persist within macrophages. By contrast, H. pylori persist extracellularly, although we discuss a possible intracellular niche as well.

  • Persistent bacterial pathogens have evolved specific mechanisms to circumvent the host immune response. We discuss some of the host factors involved in controlling bacterial replication and pathology. We also summarize some of the bacterial virulence determinants involved in this interplay with host antimicrobial mechanisms.

Abstract

Persistent bacterial infections involving Mycobacterium tuberculosis, Salmonella enterica serovar Typhi (S. typhi) and Helicobacter pylori pose significant public-health problems. Multidrug-resistant strains of M. tuberculosis and S. typhi are on the increase, and M. tuberculosis and S. typhi infections are often associated with HIV infection. This review discusses the strategies used by these bacteria during persistent infections that allow them to colonize specific sites in the host and evade immune surveillance. The nature of the host immune response to this type of infection and the balance between clearance of the pathogen and avoidance of damage to host tissues are also discussed.

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Figure 1: Persistent mycobacterial infection and the host immune response.
Figure 2: Persistent Salmonella infection.
Figure 3: Persistent Helicobacter pylori infection.
Figure 4: Balancing protective immunity and immunopathology during persistent bacterial infections.

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Acknowledgements

We are grateful to H. Rachman, S. H. E. Kaufmann, C. Cosma and L. Ramakrishnan for sharing unpublished data. We thank S. H. E. Kaufmann, C. Cosma, L. Ramakrishnan, E. Joyce, I. Brodsky, S. Merrell, R. Haas and M. Amieva for critical reading of the manuscript. Research by the authors is supported by the National Institutes of Health, the Ellison Medical Foundation, the Digestive Disease Center (to S.F.) and Deutsche Forschungsgemeinschaft (to A.M.).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, Stanford, 94305, California, USA

    Denise M. Monack, Anne Mueller & Stanley Falkow

Authors
  1. Denise M. Monack
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  2. Anne Mueller
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  3. Stanley Falkow
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Correspondence to Denise M. Monack.

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DATABASES

Entrez

Helicobacter pylori

IFN-γ

IL-2

IL-2R

IL-10

IL-12

IL-23

LRG-47

Mycobacterium marinum

Mycobacterium tuberculosis

NFAT

NOS2

Nramp1

S. typhi

S. typhimurium

TGF-β

TLR2

TLR4

TNF-α

Infectious Disease Information

HIV

salmonellosis

tuberculosis

typhoid fever

SwissProt

babA

babB

FlaA

FlaB

ICL

mig-14

rocF

TraG

VacA

virK

Glossary

INNATE IMMUNE RESPONSE

A cellular defence reaction that counteracts invading pathogens, such as bacteria and viruses. It uses interferon-dependent signalling and leads to the activation of genes that are responsible for bactericidal or antiviral responses.

ADAPTIVE IMMUNE RESPONSE

This involves specificity and immunological memory. It is mediated by T and B cells through the activation of cytotoxic CD8+ T cells for pathogen killing or by interaction with CD4+ T cells for antibody production.

RETICULOENDOTHELIAL SYSTEM

A diffuse system of cells that helps the body fight infection and eliminate cellular debris through the action of phagocytic cells (such as macrophages), Kupffer cells in the liver and reticular cells of the spleen, bone marrow and lymph nodes.

MACROPHAGES

Cells of the mononuclear-phagocyte system that can phagocytose foreign particulate material. Macrophages are present in many tissues and are important for nonspecific immune reactions.

DENDRITIC CELLS

Professional antigen-presenting cells that take up proteins and present peptide antigens to T cells in conjunction with accessory molecules that stimulate T-cell activation. They are characterized by many long, thin processes extending from the cell body.

PHAGOSOME

A membrane-bound, cytoplasmic vacuole formed around particles that are ingested by phagocytosis.

CYTOKINES

Low-molecular-weight proteins that are important for immunity, inflammation and development, and which contribute to the pathophysiology of acute and chronic infections.

α-CRYSTALLIN

The expression of this chaperonin protein is upregulated in vitro by hypoxia.

HELPER T CELLS

A subpopulation of activated CD4+ T cells that secrete characteristic cytokines and function primarily in cell-mediated responses by promoting the activation of cytotoxic T cells and macrophages.

BACILLE CALMETTE–GUÉRIN

The attenuated Mycobacterium bovis live vaccine.

DIFFERENTIAL FLUORESCENCE INDUCTION

A selection strategy used to identify bacterial genes that are preferentially expressed when a bacterium is in a particular environment. By inserting random pieces of bacterial DNA in front of a promoterless green fluorescent protein (GFP) gene, flow cytometry can be used to screen for genes expressed in specific environments.

GLYOXYLATE-SHUNT PATHWAY

A biochemical pathway that is used by plants and microorganisms to metabolize acetate or long-chain fatty acids as a source of energy.

PEYER'S PATCHES

Lymphoid nodules located in the small intestine that trap antigens from the gastrointestinal tract and provide sites where immune cells — such as B and T lymphocytes, macrophages and dendritic cells — can interact with antigen.

MAJOR HISTOCOMPATIBILITY COMPLEX

A complex of genes encoding cell-surface molecules that are required for antigen presentation to T cells.

BILIARY TRACT

Includes the gall bladder and bile ducts, which make and transport bile. Bile contains salts or detergents that disrupt bacterial membranes; it also activates autolysins that digest peptidoglycan.

MOMA2+ MACROPHAGES

MOMA2 is expressed in the cytoplasm of monocytes and macrophages. MOMA2+ macrophages can be found in the splenic red pulp, in the cortex of the thymus, in the subcapsule and medullary regions of lymph nodes and in sites of acute and chronic inflammation.

PATHOGENICITY ISLANDS

Large (10 –50-kb) insertions in the bacterial chromosome that encode virulence determinants. They are thought to be acquired by horizontal transfer.

PHAGOCYTIC OXIDASE (PHOX)

Production of reactive oxygen intermediates, which can kill bacteria directly or after reacting with chlorine, is mediated by the NADPH oxidase system located in the membrane of the macrophage and includes the PHOX enzyme.

ATROPHIC GASTRITIS

Chronic inflammation of the stomach with degeneration of the mucosa.

PANMIXIS

Mating without regard to the genetic constitution of the mate.

RANDOMLY AMPLIFIED POLYMORPHIC DNA (RAPD) PCR

A molecular technique used for the classification and comparison of different isolates of the same species. This method uses a randomly chosen oligonucleotide to prime DNA synthesis and results in strain-specific patterns of DNA products.

LEWIS BLOOD GROUP

Antigens of red blood cells, saliva and other body fluids that are specified by the Le gene and react with the antibodies designated anti-Lea and anti-Leb.

CRYPTIC PLASMIDS

Small, mobilizable genetic elements that can encode virulence factors.

CHROMOSOMAL-PLASTICITY ZONES

Segments of the chromosome that are characterized by their different G+C content, which is a hallmark of horizontally acquired sequences.

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Monack, D., Mueller, A. & Falkow, S. Persistent bacterial infections: the interface of the pathogen and the host immune system. Nat Rev Microbiol 2, 747–765 (2004). https://doi.org/10.1038/nrmicro955

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