Nectin-4-Dependent Measles Virus Spread to the Cynomolgus Monkey Tracheal Epithelium: Role of Infected Immune Cells Infiltrating the Lamina Propria

Frenzke, Marie; Sawatsky, Bevan; Wong, Xiao Xiang; Delpeut, Sébastien; Mateo, Mathieu; Cattaneo, Roberto; Messling, Véronika von

doi:10.1128/jvi.03037-12

Cited by 49 publications

(64 citation statements)

References 36 publications

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“…These MV-infected immune cells contacting or infiltrating into respiratory epithelium spread infection to PVRL4 + epithelial cells in the late stages of the disease (Frenzke et al, 2013;Ludlow et al, 2013). Macaques provide an excellent natural model in which to investigate the late stages of measles as a number of outbreaks have been reported in primate colonies with extensive chains of transmission between animals (Choi et al, 1999;MacArthur et al, 1979;Willy et al, 1999).…”

Section: Measles Virus (Mv) a Morbillivirus In The Familymentioning

confidence: 99%

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

Ludlow

Vries

Lemon

et al. 2013

Journal of General Virology

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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.

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Section: Measles Virus (Mv) a Morbillivirus In The Familymentioning

confidence: 99%

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

Ludlow

Vries

Lemon

et al. 2013

Journal of General Virology

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“…In addition to infection of a group of eight squirrel monkeys with the wild-type eGFPexpressing MeV, a group of six animals was inoculated with its nectin-4-blind derivative, MeV-N4 blind (13). Again, this group was infected with the same dose of virus from the same batch used in a previous cynomolgus macaque study (10). In contrast to the wild-type virus, MeV-N4 blind did not cause any clinical signs apart from a mild rash ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In macaques, the viral loads in PBMCs and the extents of immunosuppression were also similar for the two viruses, and the nectin-4-blind derivative was unable to infect epithelial cells. However, the impact on clinical disease remained unclear due to the overall mild course (10,13). The comparison of the two viruses in squirrel monkeys demonstrates that the causal link between nectin-4-mediated epithelial cell infection and clinical disease is shared by MeV and CDV and most likely all morbilliviruses.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we infected squirrel monkeys with the recombinant wild-type strain IC323, which expresses the eGFP gene from an additional transcription unit inserted upstream of the nucleocapsid (N) gene (20). Pathogenesis of this virus has been extensively characterized in rhesus and cynomolgus macaques, where only minimal clinical signs and mild and transient immunosuppression were monitored (10). To ensure a fair side-by-side comparison of MeV pathogenesis in different species, we infected the squirrel monkeys with the same dose of virus from the same batch that we previously used to infect cynomolgus macaques (10).…”

Section: Resultsmentioning

confidence: 99%

“…In recent years, several important insights into the early stages of MeV pathogenesis have been gained from such studies in rhesus or cynomolgus macaques (7)(8)(9)(10)(11)(12)(13)(14)(15). After inoculation via aerosol, which most closely reproduces natural infection, virus is first detected in immune cells of the lower respiratory tract (11).…”

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confidence: 99%

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Nectin-4 Interactions Govern Measles Virus Virulence in a New Model of Pathogenesis, the Squirrel Monkey (Saimiri sciureus)

Delpeut

Sawatsky

Wong

et al. 2017

J Virol

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In addition to humans, only certain nonhuman primates are naturally susceptible to measles virus (MeV) infection. Disease severity is species dependent, ranging from mild to moderate for macaques to severe and even lethal for certain New World monkey species. To investigate if squirrel monkeys (Saimiri sciureus), which are reported to develop a course of disease similar to humans, may be better suited than macaques for the identification of virulence determinants or the evaluation of therapeutics, we infected them with a green fluorescent protein-expressing MeV. Compared to cynomolgus macaques (Macaca fascicularis) infected with the same virus, the squirrel monkeys developed more-severe immunosuppression, higher viral load, and a broader range of clinical signs typical for measles. In contrast, infection with an MeV unable to interact with the epithelial receptor nectin-4, while causing immunosuppression, resulted in only a mild and transient rash and a short-lived elevation of the body temperature. Similar titers of the wild-type and nectin-4-blind MeV were detected in peripheral blood mononuclear cells and lymph node homogenates, but only the wild-type virus was found in tracheal lavage fluids and urine. Thus, our study demonstrates the importance of MeV interactions with nectin-4 for clinical disease in the new and better-performing S. sciureus model of measles pathogenesis. IMPORTANCEThe characterization of mechanisms underlying measles virus clinical disease has been hampered by the lack of an animal model that reproduces the course of disease seen in human patients. Here, we report that infection of squirrel monkeys (Saimiri sciureus) fulfills these requirements. Comparative infection with wild-type and epithelial cell receptor-blind viruses demonstrated the importance of epithelial cell infection for clinical disease, highlighting the spread to epithelia as an attractive target for therapeutic strategies.

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Pathological consequences of systemic measles virus infection

Ludlow

McQuaid²,

Milner

et al. 2014

The Journal of Pathology

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The identification of poliovirus receptor-like 4 (PVRL4) as the second natural receptor for measles virus (MV) has closed a major gap in our understanding of measles pathogenesis, and explains how this predominantly lymphotropic virus breaks through epithelial barriers to transmit to a susceptible host. Advances in the development of wild-type, recombinant MVs which express fluorescent proteins making infected cells readily detectable in living tissues and animals, has also increased our understanding of this important and highly transmissible human disease. Thus, it is timely to review how these advances have provided new insights into MV infection of immune, epithelial and neural cells. This demands access to primate samples that help us understand the early and acute stages of the disease, which are challenging to dissect due to the mild/self-limiting nature of the infection. It also requires well-characterized and rather rare human tissue samples from patients who succumb to neurological sequelae to help study the consequences of the long-term persistence of this RNA virus in vivo. Collectively, these studies have provided unique insights into how the use of two cellular receptors, CD150 and PVRL4, governs the in vivo tissue-specific temporal patterns of virus spread and resulting pathological lesions. Analysis of tissue samples has also demonstrated the importance of differing mechanisms of virus cell-to-cell spread within lymphoid, epithelial and neural tissues in the dissemination of MV during acute and long-term persistent infections. Given the incentive to eradicate MV globally, and the inevitable question as to whether or not vaccination should cease in light of the existence of closely related morbilliviruses, a thorough understanding of measles pathological lesions is essential.

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Nectin-4-Dependent Measles Virus Spread to the Cynomolgus Monkey Tracheal Epithelium: Role of Infected Immune Cells Infiltrating the Lamina Propria

Cited by 49 publications

References 36 publications

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

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

Nectin-4 Interactions Govern Measles Virus Virulence in a New Model of Pathogenesis, the Squirrel Monkey (Saimiri sciureus)

Pathological consequences of systemic measles virus infection

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