Cytomegalovirus Infection and Inflammation in Developing Brain

Abstract

Human cytomegalovirus (HCMV) is a highly prevalent herpesvirus that can cause severe disease in immunocompromised individuals and immunologically immature fetuses and newborns. Most infected newborns are able to resolve the infection without developing sequelae. However, in severe cases, congenital HCMV infection can result in life-threatening pathologies and permanent damage of organ systems that possess a low regenerative capacity. Despite the severity of the problem, HCMV infection of the central nervous system (CNS) remains inadequately characterized to date. Cytomegaloviruses (CMVs) show strict species specificity, limiting the use of HCMV in experimental animals. Infection following intraperitoneal administration of mouse cytomegalovirus (MCMV) into newborn mice efficiently recapitulates many aspects of congenital HCMV infection in CNS. Upon entering the CNS, CMV targets all resident brain cells, consequently leading to the development of widespread histopathology and inflammation. Effector functions from both resident cells and infiltrating immune cells efficiently resolve acute MCMV infection in the CNS. However, host-mediated inflammatory factors can also mediate the development of immunopathologies during CMV infection of the brain. Here, we provide an overview of the cytomegalovirus infection in the brain, local immune response to infection, and mechanisms leading to CNS sequelae.

Keywords: CMV tropism; central nervous system; congenital HCMV infection; cytomegalovirus; immune response; inflammation; latency; mouse cytomegalovirus.

Figure 1

Cytomegalovirus infection in developing brain. Cytomegalovirus (CMV) dissemination to the central nervous system (CNS) is secondary to peripheral organ infection (1). Upon reaching the brain, CMV is hypothesized to cross the blood–brain barrier (BBB) by either cell-associated (2a) or cell-free form (2b). Monocytes are proposed to mediate cell-associated passage across the BBB. Upon crossing of the BBB, CMV infects resident cells (3). Apart from oligodendrocytes, CMV infection of resident CNS cells was confirmed in vivo. CMV DNA was detected in cerebrospinal fluid (CSF) of congenitally infected infants and neural stem precursor cells (NSPCs), abundant in subventricular zones (SVZ), are a prominent target of CMV infection. Figure was created with Biorender.

Figure 2

Immune response to cytomegalovirus infection in the brain. (a) Acute infection. Upon crossing of the blood–brain barrier (BBB), cytomegalovirus (CMV) infects resident cells (1). Astrocyte-derived chemokines recruit microglia to the infection site (2a). Microglia are activated via pattern recognition receptors and cytokines. Activated microglia produce proinflammatory cytokines (2b), which mediate immune cell recruitment into the brain (3) and orchestrate immune cell response (4). Infiltrating NK cells and ILC1 cells produce IFN-γ and myeloid cells produce TNF-α, leading to organ-wide polarization of microglia (5); infiltrating T cells provide direct control of productive infection (6). CD8⁺ and CD4⁺ T cells recognize virus-infected cells in the context of MHC I and MHC II molecules and provide virus control by cytolytic mechanisms (gzmB) or by non-cytolytic mechanisms (IFN-γ). (b) Latent infection. Following resolution of acute CMV infection, T cells are retained in the brain as tissue-resident cells (T_RM) and control latent/reactivating CMV. CD8⁺ T_RM cells are characterized by expression of CD69 and integrin CD103, while CD4⁺ T_RM cells express CD69 and CD11a. Both cytolytic mechanisms (gzmB) and cytokines (IFN-γ) could mediate the control of latent and reactivating CMV in the CNS. T_RM cells are suggested to persist in the brain of mice for a lifetime without or with minimal replenishment from the circulation. Activated microglia probably contribute to maintenance and functional capacity of TRM cells in the brain. Figure was created with Biorender.