Intracellular Pathogens: Host Immunity and Microbial Persistence Strategies

Abstract

Infectious diseases caused by pathogens including viruses, bacteria, fungi, and parasites are ranked as the second leading cause of death worldwide by the World Health Organization. Despite tremendous improvements in global public health since 1950, a number of challenges remain to either prevent or eradicate infectious diseases. Many pathogens can cause acute infections that are effectively cleared by the host immunity, but a subcategory of these pathogens called "intracellular pathogens" can establish persistent and sometimes lifelong infections. Several of these intracellular pathogens manage to evade the host immune monitoring and cause disease by replicating inside the host cells. These pathogens have evolved diverse immune escape strategies and overcome immune responses by residing and multiplying inside host immune cells, primarily macrophages. While these intracellular pathogens that cause persistent infections are phylogenetically diverse and engage in diverse immune evasion and persistence strategies, they share common pathogen type-specific mechanisms during host-pathogen interaction inside host cells. Likewise, the host immune system is also equipped with a diverse range of effector functions to fight against the establishment of pathogen persistence and subsequent host damage. This article provides an overview of the immune effector functions used by the host to counter pathogens and various persistence strategies used by intracellular pathogens to counter host immunity, which enables their extended period of colonization in the host. The improved understanding of persistent intracellular pathogen-derived infections will contribute to develop improved disease diagnostics, therapeutics, and prophylactics.

Figure 1

Schematic representation of the host immune response against microbial pathogens. Microbial pathogens or antigens can be taken up by the antigen-presenting cells, mostly dendritic cells (DCs), once they breach the epithelial barrier. Antigens are presented to the naive T cells by the activated DCs through major histocompatibility complex–T cell receptor interaction, which leads to activation and expansion of antigen-specific effector T cells (Teff). Teff differentiate into one of the different subtypes, e.g., helper T cells (Th)1, Th2, follicular helper T cells (Tfh), Th17, or regulatory T cells (Tregs), depending on the cytokine milieu of the microenvironment. Th1 cells activate macrophages or CD8⁺ T cells through production of IFN-γ. Activated macrophages fuse their lysosomes more efficiently to phagosomes, exposing intracellular microbes to a variety of microbicidal lysosomal enzymes and toxic oxygen and nitrogen metabolites. Cytotoxic T cells (CTL) destroy pathogens through release of perforins and granzymes or induce apoptosis of infected cells. Th2 and Tfh cells activate B cells through production of cytokines and induce the differentiation of B cells into plasma cells, antibody class switching, and affinity maturation of antibodies, which remove the pathogen by neutralization, opsonization, and phagocytosis. Th17 cells participate in neutrophil activation and immune regulation by producing cytokine IL-17A, which is required for protection against extracellular and some intracellular pathogens. Tregs regulate immune responses to pathogens and maintain self-tolerance by negatively regulating Th1 and Th2 cells, e.g., by producing cytokines IL-10 and TGF-β. Innate immune cells such as eosinophils, basophils, and mast cells play an important role in protection against parasitic infections including helminth infections. Natural killer (NK) and natural killer T (NKT) cells, which form a bridge between innate and adaptive immunity, also contribute to antibacterial and antiviral immunity. NK cells have similar functions as the CTL while NKT cells produce cytokines to execute their killing functions.

Figure 2

Schematic representation of the mechanisms of persistence of selected intracellular pathogens. Left: an overview of the various mechanisms used by pathogens to overcome innate and adaptive immune responses. The major strategies are discussed in more detail in the text. Right: evasion strategies of various phagocytic mechanisms by selected intracellular pathogens. Viruses such as influenza virus are able to inhibit the activation of antiviral mechanisms, such as the production of interferon upon viral infection, and enter the nucleus. Mycobacterium tuberculosis after phagocytosis acquires the early endosome marker Rab5, which blocks fusion with the lysosome, and the mycobacteria replicate in this early endosome. Legionella pneumophila resides and multiplies in vacuoles that acquire Rab1 and secretes effector molecules via its type IV secretion system, which inhibits phagolysosome formation. Listeria monocytogenes-engulfed phagosome undergoes acidification, which perforates the phagosomal membrane and the bacteria escape into the cytosol, where they move within and then among cells with actin polymerization. Chlamydia spp. are present as nonreplicating infectious “elementary body” and intracytoplasmic replicating noninfectious “reticulate body.” The elementary body induces its own endocytosis upon exposure to host cells and survives and multiplies inside phagolysosome before infecting the new host. Coxiella burnetii and Brucella abortus are present inside a vacuole, which becomes acidic and acquires Rab5 followed by Rab7 that prevents phagolysosome formation. The Francisella tularensis phagosome acquires Rab5 (early endosome) and then Rab7 (late endosome). Late endosome is not acidified, which disrupts the phagosomal membrane discharging the bacteria into the cytosol. These vacuoles fuse with the endoplasmic reticulum, which allow bacterial replication. Leishmania spp. phagosome becomes acidic phagolysosome, which bears Rab7, and the parasite survives and multiplies inside the phagolysosome.