In addition to its critical function of protecting us against pathogens, an essential feature of the immune system is its compartmentalization, which is crucial for maintaining immune homeostasis in different organs and tissues. The immune system must be able to detect pathogen invasion or cell/tissue damage in every tissue and organ of our body. In contrast to the systemic immune response, whose primary task is to prevent the system-wide spread of a pathogen, the immune response in individual tissues or organs needs to maintain the integrity, preserve homeostasis and prevent immunopathological tissue damage of these organs. Different tissues require different strategies so it is not surprising that the tissue-specific immune cells in different tissues display various phenotypic and functional characteristics. These functional characteristics are modulated by the host tissue itself - organs and tissue-specific factors appear to instruct regional immune responses. This special issue of the CMI includes several articles that describe the current state and progress in understanding the immune response to viruses at the systemic and tissue levels, including metabolic aspects of systemic and tissue-specific immune response.

Dr. Stipan Jonjić

Many viruses can infect the CNS, leading to viral encephalitis with diverse neurological outcomes and potentially life-threatening conditions. The article by Pavlou and Mulenge et al., provides a comprehensive overview of the antiviral response in the CNS to various viruses, focusing on the roles of myeloid cells and CD8 T cell responses [1]. The heterogeneity of microglial subsets and their diverse responses are addressed, highlighting both the protective and pathological roles of microglia during viral encephalitis. The review also emphasizes the importance of CD8 T cells in resolving acute CNS infections. As always, CD8 T cells can be both forces of protection and damage: CD8 T cell-mediated IFN-γ production during chronic CNS infections can result in CNS pathology and cognitive impairments, partly due to chronic microglia stimulation. Overall, this review elucidates the mechanisms of immune control of viral infections and the neuropathological outcomes of infection.

The article by Mihalić and Železnjak et al. represents a comprehensive overview of cytomegalovirus (CMV) infection and tissue-specific immune responses in numerous organs including the infection dynamics, the types of infected cells, and the organ-specific immune response that either exacerbates or controls infection [2]. Both human infection and animal models of CMV infection are discussed, depending on the availability of data. While harmless to immunocompetent hosts, CMV causes dramatic pathology in immunodeficient and immunologically immature individuals. Moreover, CMV infects most organs and tissues making it an excellent model for studying tissue-specific antiviral responses. Finally, like other herpesviruses, it establishes life-long latency from which periodic reactivation can occur. One of the main characteristics of the CMV genome is the presence of a large number of immune evasion genes whose products manipulate and exploit essentially all components of the innate and adaptive immune response, which in turn likely causes the immune response variation in different tissues. Although initial studies revealed that CD8 T cells play a vital role in controlling infections in most tissues and organs, in others, most notably the salivary glands, they are dispensable, and CD4 T cells are the main controllers of infection. Recent research in a mouse model of CMV infection of the ovaries demonstrated that CMV infection could compromise pregnancy and revealed innate immune mechanisms that protect fertility from widespread viral infections. Congenital human CMV infection is the leading viral cause of neurodevelopmental disorders, brain injury, mental retardation, and sensorineural hearing loss. In the CNS, congenital infection of newborn mice with mouse CMV results in activation of microglia and infiltration of NK/ILC cells in the brain, as well as in IFNγ-mediated neuropathology. However, acute infection is resolved in the CNS by T cells, which reside within the brain as tissue-resident memory T cells securing efficient surveillance of potential future virus reactivation. Thus, CMV is not only an excellent model virus, but a relevant human pathogen for which treatments are insufficient and vaccine is still lacking. Understanding tissue responses and pathologies is a necessary next step towards development of better interventions.

It is well established that mucosal immunity plays a critical role in the pathogenesis and control of different viruses. Al-Talib et al. review the roles of T-cell subsets in chronic viral infections of mucosal tissues [3] focusing on the pathogenesis and control of two important, persistent viruses, human CMV and human immunodeficiency virus (HIV). The article describes in detail the selective roles of conventional and non-classical T lymphocyte subpopulations in the context of developing vaccines designed to induce mucosal immunity against viruses, and the authors emphasize the importance of experimental models to test administration routes and determine the optimal mucosal T-cell response induced by vaccination.

The review by Melo-Silva and Sigal explores the intricate innate immune responses orchestrated within draining LN (dLN) that contain primary viral infections, as well as the role of memory CD8 T cells following secondary infection or CD8 T cell vaccination [4]. LNs are strategically positioned and have the appropriate cellular composition to serve as sites of initiation of adaptive immune response against invading pathogens. Especially for lymph-borne viruses, which disseminate from the entry site to other tissues through the lymphatic system, immune cells in the dLN also play critical roles in curbing systemic viral dissemination during primary and secondary infections. Lymph-borne viruses in tissues can be transported to dLNs as free virions in the lymph or within infected cells. The innate immune response mechanisms involve cellular crosstalk between infected and bystander innate immune cells that ultimately produce type I interferons and other cytokines and recruit inflammatory monocytes and NK cells to restrict systemic viral spread during primary infections and prevent severe disease. Additionally, the memory CD8 T cells that reside or rapidly migrate to the dLN can contribute to disease prevention during secondary viral infections.

Type I interferon (IFN-I) production in various tissues is vital for both homeostatic and pathological conditions and mounting adequate response early after infection. In the review by Ngo et al., the importance of plasmacytoid dendritic cells (pDCs) as a source of IFN-I, their tissue-dependent regulation, and their contribution to host resistance are discussed [5]. pDCs are found in both lymphoid and non-lymphoid tissues and can migrate to other organs upon infection, stimulating innate and adaptive immunity in an IFN-I-dependent manner. However, the abundance of pDCs and the production of the IFN-I subfamily largely depend on the tissue properties and the type and nature of the infection. One essential characteristic of pDCs critical for host defense against viral infections is their ability to induce an IFN-dependent, infection-resistant state in almost all host cells. Conversely, pDCs can also contribute to the pathology of certain chronic or respiratory viral infections.

The review article by Sytse J. Piersma deals with various aspects of anti-viral defense mediated by innate lymphoid cells (ILC) in both humans and mice and describes key phenotypical and transcriptional features and their individual functions, primarily in the context of viral infections [6]. In addition, the antiviral activities of ILCs in several organ systems that are most prone to viral infections are described. The first part of the article is an overview of the differences among subgroups of ILCs and their selective function in infections with different viruses in tissues. Although different members of the ILC family contribute to antiviral immunity, it appears that individual subpopulations of ILC use unique effector functions within the tissue microenvironment. Moreover, there is strong evidence for the plasticity of these cells, i.e., different ILC subtypes can acquire the characteristics of other subtypes, indicating that ILCs can adapt to specific needs within the tissue microenvironment.

In addition to its critical function in host defense against pathogens, the immune system maintains homeostasis by sensing metabolic changes. The review by Wensveen et al. addresses the immunometabolic changes in the response to infection [7]. After encountering a pathogen, the activated immune system mediates many changes in local and systemic metabolism. Since the metabolic changes caused by infection are perceived as pathology because they make us feel sick, the authors use the term “metabolism of sickness”, emphasizing that the complex metabolic changes caused by infection are expedient in terms of favoring protection from pathogens. Homeostasis is regulated at multiple levels, but its systemic coordination is ensured by continuous measurement and corrective action of the nervous and endocrine systems. The reasons why changes in metabolism caused by infection have a cost for the normal biology of the organism are described. While the endocrine and nervous systems dominantly regulate systemic homeostasis, the immune system “assesses” the significance and extent of the threat and the need for a small local or large metabolic response, whereby the type and intensity of metabolic changes are adapted to the threat level and depend on the signals of immune cells in the tissue. The authors also discuss how infection affects key organ systems involved in regulating metabolic homeostasis.

In summary, this special issue of CMI contains discussions and updates that address the many peculiarities of the immune response in tissues and organs following the infection with various viruses. The review articles address the complex theme of tissue-specific immune responses from various angles and from the perspective of different virus infections. I am confident that this collection will foster the exchange of new ideas and the development of new research avenues and will provide the basis for the development of new treatment and prevention strategies.