Cytomegaloviruses and Macrophages—Friends and Foes From Early on?

Abstract

Starting at birth, newborn infants are exposed to numerous microorganisms. Adaptation of the innate immune system to them is a delicate process, with potentially advantageous and harmful implications for health development. Cytomegaloviruses (CMVs) are highly adapted to their specific mammalian hosts, with which they share millions of years of co-evolution. Throughout the history of mankind, human CMV has infected most infants in the first months of life without overt implications for health. Thus, CMV infections are intertwined with normal immune development. Nonetheless, CMV has retained substantial pathogenicity following infection in utero or in situations of immunosuppression, leading to pathology in virtually any organ and particularly the central nervous system (CNS). CMVs enter the host through mucosal interfaces of the gastrointestinal and respiratory tract, where macrophages (MACs) are the most abundant immune cell type. Tissue MACs and their potential progenitors, monocytes, are established target cells of CMVs. Recently, several discoveries have revolutionized our understanding on the pre-and postnatal development and site-specific adaptation of tissue MACs. In this review, we explore experimental evidences and concepts on how CMV infections may impact on MAC development and activation as part of host-virus co-adaptation.

Cytomegalovirus transmission in mismatched solid organ transplant recipients: Are factors other than anti-viral prophylaxis at play?

“…18,19 Lytic gene expression and infectious virus production in alveolar macrophages of CMV seropositive patients who had neither CMV DNAemia nor an inflammatory state have been observed 20 suggesting the alveolar macrophage may be an additional site of latent or persistent CMV infection in the lung. We hypothesize that in addition to latent load, organ-specific differences in donor tissue macrophage survival related to their ontogeny [21][22][23][24] and the dynamics of developing recipient chimerism in the donor organ 22,25 as macrophages are replenished by recipient monocytes when organs are injured at transplantation may contribute to differences in organspecific CMV transmission rates. 26 Recipient microchimerism may evolve slowly.…”

Protective and pathological roles of regulatory immune cells in human cytomegalovirus infection following hematopoietic stem cell transplantation

“…Therefore, tissue-resident macrophages are immediate targets of HCMV infection in various tissues. 70 Though these cells have been terminally differentiated, they are capable of altering their function in accordance to environmental stimuli, like those induced in infections. 71 Polarization of macrophages towards either pro-or antiinflammatory state prior to viral exposure, changes their vulnerability to infection.…”

“…These sites are occupied by tissue‐resident macrophages. Therefore, tissue‐resident macrophages are immediate targets of HCMV infection in various tissues 70 . Though these cells have been terminally differentiated, they are capable of altering their function in accordance to environmental stimuli, like those induced in infections 71 .…”

MHC class Ia molecules facilitate MCK2-dependent MCMV infection of macrophages and virus dissemination to the salivary gland

“…Importantly, MCMV entry into macrophages and viral dissemination from the lungs is dependent on MCMV-encoded chemokine 2 (MCK2) (Ma et al, 2021; Stahl et al, 2015), a CC-chemokine-like product of spliced ORF m131/129 (MacDonald et al, 1999). It has been reported that MCK2 attracts monocytes to the site of infection through CX3CR1 signaling (Daley-Bauer et al, 2014) and enables the virus to disseminate by abortively infected myeloid cells, including monocytes, macrophages, and/or dendritic cells (Baasch et al, 2020; Farrell et al, 2017; Zhang et al, 2021). Upon intranasal infection, MCMV disseminates primarily to salivary glands (Oduro et al, 2016; Stahl et al, 2015), an organ that allows viral persistence and shedding for transmission to new hosts.…”