Infection of lymphoid tissues in the macaque upper respiratory tract contributes to the emergence of transmissible measles virus

Abstract

Measles virus (MV), a member of the family Paramyxoviridae, remains a major cause of morbidity and mortality in the developing world. MV is spread by aerosols but the mechanism(s) responsible for the high transmissibility of MV are largely unknown. We previously infected macaques with enhanced green fluorescent protein-expressing recombinant MV and euthanized them at a range of time points. In this study a comprehensive pathological analysis has been performed of tissues from the respiratory tract around the peak of virus replication. Isolation of virus from nose and throat swab samples showed that high levels of both cell-associated and cell-free virus were present in the upper respiratory tract. Analysis of tissue sections from lung and primary bronchus revealed localized infection of epithelial cells, concomitant infiltration of MV-infected immune cells into the epithelium and localized shedding of cells or cell debris into the lumen. While high numbers of MV-infected cells were present in the tongue, these were largely encapsulated by intact keratinocyte cell layers that likely limit virus transmission. In contrast, the integrity of tonsillar and adenoidal epithelia was disrupted with high numbers of MV-infected epithelial cells and infiltrating immune cells present throughout epithelial cell layers. Disruption was associated with large numbers of MV-infected cells or cell debris 'spilling' from epithelia into the respiratory tract. The coughing and sneezing response induced by disruption of the ciliated epithelium, leading to the expulsion of MV-infected cells, cell debris and cell-free virus, contributes to the highly infectious nature of MV.

The Tumor-Associated Marker, PVRL4 (Nectin-4), Is the Epithelial Receptor for Morbilliviruses

“…In contrast, MeV preferentially infects differentiated primary epithelial cells via the basolateral route, which is consistent with polarized expression of PVRL4 along the basolateral surface of pseudostratified ciliated epithelial cells in the trachea and nasal concha [51,52,53,54]. PVRL4 actually plays a key role in virus spread from immune to epithelial cells [54,55,56]. A study with monkeys highlights the fact that MeV preferentially infects the basolateral surface of well-differentiated human airway epithelia via the migration of CD150-expressing myeloid cells into the tracheal epithelium [55].…”

Delineating morbillivirus entry, dissemination and airborne transmission by studying in vivo competition of multicolor canine distemper viruses in ferrets

“…Two cellular receptors involved in morbillivirus infection have been identified: signaling lymphocyte activation molecule family member 1 (SLAM/F1, or CD150), expressed by subsets of thymocytes, dendritic cells (DCs), hematopoietic stem cells, macrophages, T- and B-lymphocytes [14], and nectin cell adhesion molecule 4 (nectin-4, previously known as poliovirus receptor-related 4), expressed at the adherens junction complex of epithelial cells [15, 16]. Both receptors play a crucial role in viral pathogenesis (reviewed in [17]), with CD150-mediated infection being critical for entry and dissemination [18, 19] and nectin-4-mediated infection critical for virus transmission [20, 21]. …”

The V Protein of Canine Distemper Virus Is Required for Virus Replication in Human Epithelial Cells

“…SLAM is expressed on cells of the immune system, and nectin-4 is expressed in the epithelial cells of various organs [23]. Nectin-4 is exclusively expressed at the basolateral surface of differentiated epithelial cells, and thus epithelial cells can only be infected by immune cells infiltrating the epithelial submucosa [24], [25]. Although the abilities to use SLAM and nectin-4 are shared by MV and CDV, CDV preferentially uses dog SLAM (dSLAM) [18], [26] and shows a disability in using human SLAM (hSLAM) [13], [27]–[30].…”