Immune surveillance of cytomegalovirus in tissues

Abstract

Cytomegalovirus (CMV), a representative member of the Betaherpesvirinae subfamily of herpesviruses, is common in the human population, but immunocompetent individuals are generally asymptomatic when infected with this virus. However, in immunocompromised individuals and immunologically immature fetuses and newborns, CMV can cause a wide range of often long-lasting morbidities and even death. CMV is not only widespread throughout the population but it is also widespread in its hosts, infecting and establishing latency in nearly all tissues and organs. Thus, understanding the pathogenesis of and immune responses to this virus is a prerequisite for developing effective prevention and treatment strategies. Multiple arms of the immune system are engaged to contain the infection, and general concepts of immune control of CMV are now reasonably well understood. Nonetheless, in recent years, tissue-specific immune responses have emerged as an essential factor for resolving CMV infection. As tissues differ in biology and function, so do immune responses to CMV and pathological processes during infection. This review discusses state-of-the-art knowledge of the immune response to CMV infection in tissues, with particular emphasis on several well-studied and most commonly affected organs.

Keywords: Cytomegalovirus; HCMV; Immune response; MCMV; Pathogenesis; Tissue.

Fig. 1

Immune response to CMV infection in spleen. A MCMV primarily enters the spleen through the marginal zone around 6 h p.i. where it infects ER-TR7+ stromal cells and activates the LTβR pathway, which depends on the interaction between LTβR-expressing stromal cells and LT-αβ+ B cells. Activation of the LTβR pathway induces NF-κB signaling in infected stromal cells, resulting in the production of type I interferons (IFNαβ). B At 36-48 h p.i. MCMV spreads into the red pulp and, in MCMV-sensitive strains, infiltrates the white pulp as well. pDCs from the red pulp start accumulating in the MZ, detecting MCMV via a TLR-dependent mechanism, leading to sustained production of IFNαβ locally and systemically. IFNαβ and IL-12, IL-15, and IL-18, also produced by pDCs and other immune cells, promote NK cell cytotoxicity. At 48 h p.i. there is a widespread infection in the spleen and changes in the spleen’s microarchitecture are starting to be evident. cDC1s form clusters with activated NK cells in an XCR1-dependent manner, delivering IL-12 and IL-15 to NK cells directly. Consequently, NK cells secrete GM-CSF, promoting the re-localization of cDC1 into the T cell zone of the white pulp, where they initiate the priming of CD8 T cells

Fig. 2

Immune response to CMV infection in the lungs. A Nodular inflammatory focus in the lungs. In the lungs, CMV infects alveolar macrophages (AMs), endothelial cells, fibroblast-like cells, and dendritic cells. NIFs form within the infected lung as sites of CMV control and contain different leukocyte populations, such as monocytes, neutrophils, NK cells, and T cells. B Control of CMV infection in the lungs. Antigen-presenting cells (APCs) present viral antigens to infiltrating T cells via MHC-I and MHC-II molecules. T cells, mainly CD8 T cells supported by CD4 T cells, produce IFNγ and cytolytic granules to control lung infection. Additionally, NK cells also contribute to virus control in an IFNγ-dependent manner. IL-22, which is produced by NK and T cells, recruits neutrophils at the site of infection. Neutrophils exert their antiviral effects in a TRAIL-dependent manner

Fig. 3

Immune response to CMV infection in the liver. A Innate immune response in the liver. Kupffer cells produce type I interferon (IFNαβ) in response to infection, stimulating the production of MCP-1. MCP-1 is critical for recruiting inflammatory macrophages that produce MIP-1α to recruit NK cells to sites of infection. NK cells control the virus in the liver in an IFNγ-dependent manner but can also produce TNFα to sustain virus infection. Conventional dendritic cells (cDCs) produce IL-12 to promote IFNγ production by ILC1s. B Adaptive immune response in the liver. CD8 T cells mediate the control of CMV infection in the liver by exhibiting cytotoxic activity. However, the CD8 T cell response to infection in the liver can be exaggerated and can lead to liver pathology. Regulatory T cells (Tregs) and activated NK cells can suppress the pathological response of CD8 T cells to CMV infection in the liver. Tregs (CD4⁺Foxp3⁺ T cells) strongly upregulate the expression of ST-2 receptors and infiltrate the liver in an IL33-dependent manner. IL-33 is produced by F4/80⁺ macrophages. An additional layer of control is exerted by activated NK cells that produce IL-10 and perforin to suppress immunopathology mediated by CD8 T cells in the liver

Fig. 4

Immune response to CMV infection in the salivary glands. CMV reaches the salivary gland via antigen-presenting cells: monocytes following i.p. or i.v. infection or DCs following i.n. infection. Numerous immune cells are recruited to CMV-infected salivary glands; however, unlike in any other organ, the CD4 T cells control the infection. A CD8 T cells are recruited to infected SGs and secrete IFNγ; however, they are unable to recognize infected cells because acinar endothelial cells express very low levels of MHC-I and local APCs are unable to cross-present antigens. CD4 and CD8 T cells are likely recruited by proinflammatory cytokines secreted by APCs and infected epithelial acinar cells. B CD4 T-cell immune responses in the SG. In addition to IFNγ/TNFα-secreting CD4 T cells, which control infection, IL-10-secreting CD4 T cells are recruited by IFN-I with delayed kinetics compared with IFNγ/TNFα-secreting CD4 T cells and cause virus persistence. IL-10 CD4 T cells are subsequently controlled by Tregs. Activated CD4 T cells are also regulated by NK cells, which limit their number and prevent immune-mediated pathology (e.g., Sjogren’s syndrome). At later stages of infection, M09-specific CD4 T cells accumulate in SGs and are required for virus clearance

Fig. 5

Immune response to congenital CMV infection in the brain. A Innate immune response. CMV crosses the blood‒brain barrier (BBB) in a cell-free or cell-associated manner. CMV can infect various resident cells in the CNS, with astrocytes reported as a major infected cell population. Infection results in the production of various proinflammatory cytokines and chemokines that promote microglia activation and the recruitment of peripheral immune cells to the CNS. Monocytes, macrophages, NK cells, and ILCs are the first cell populations to infiltrate the infected CNS. Monocytes and NK cells produce TNFα and IFNγ, respectively, and promote microglial activation. B Adaptive immune response and viral clearance. Activated microglia induce MHC-I and MHC-II and produce chemokines, mainly CXCL9 and CXCL10, to attract T cells to the inflamed CNS. CD4 and CD8 T cells infiltrate the CNS, recognize infected cells in an MHC-I- and MHC-II-dependent manner, and control infection by producing IFNγ and granzyme B. C Control of latent and reactivating viruses. After productive infection in the CNS is resolved, the virus establishes a latent infection. T cells are tissue-resident memory T (T_RM) cells that express CD69 and CD103 (CD8 T_RM) as well as CD69 and CD11a (CD4 T_RM) and are essential for the control of latent and reactivating viruses in the brain