Myeloid Infection Links Epithelial and B Cell Tropisms of Murid Herpesvirus-4

bHuman gammaherpesviruses cause morbidity and mortality associated with infection and transformation of lymphoid and endothelial cells. Knowledge of cell types involved in virus dissemination from primary virus entry to virus latency is fundamental for the understanding of gammaherpesvirus pathogenesis. However, the inability to directly trace cell types with respect to virus dissemination pathways has prevented definitive conclusions regarding the relative contribution of individual cell types. Here, we describe that the route of infection affects gammaherpesvirus dissemination pathways. We constructed a recombinant murine gammaherpesvirus 68 (MHV-68) variant harboring a cassette which switches fluorescent markers in a Cre-dependent manner. Since the recombinant virus which was constructed on the wild-type background was attenuated, in this study we used an M1-deleted version, which infected mice with normal kinetics. Infection of Cre-transgenic mice with this convertible virus was used to estimate the quantitative contribution of defined cell types to virus productivity and dissemination during the acute phase of MHV-68 infection. In systemic infection, we found splenic vascular endothelial cells (EC) among the first and main cells to produce virus. After local infection, the contribution of EC to splenic virus production did not represent such early kinetics. However, at later time points, B cell-derived viruses dominated splenic productivity independently of systemic or local infection. Systemic versus local infection also governed the cell types involved in loading peritoneal exudate cells, leading to latency in F4/ 80-and CD11b-positive target cells. Systemic infection supported EC-driven dissemination, whereas local infection supported B cell-driven dissemination.

Section: Discussionsupporting

confidence: 50%

Systemic and Local Infection Routes Govern Different Cellular Dissemination Pathways during Gammaherpesvirus InfectionIn Vivo

Vidy

Sacher

Adler

et al. 2013

“…However, the immune system already efficiently channels foreign antigens to myeloid cells. MuHV-4 efficiently targets dendritic cells and macrophages without an obvious need for further recruitment (31,44), and the MCMV MCK2 made little obvious contribution to myeloid cell recruitment into lungs: its disruption reduced Gr-1 ϩ cell numbers only transiently in BALB/c mice and had no significant effect in C57BL/6 mice, nor was the level of viremia during the acute phase of infection reduced. Thus, the salivary infection defect of MCK2 Ϫ MCMV may reflect that MCK2 functions after dissemination (18); for example, its chemokine function could have more of an impact in less inflammatory settings.…”

Section: Discussionmentioning

confidence: 99%

“…MCMV strain K181 with a premature stop codon in m131 (18) and other gL-positive (gL ϩ ) MCMVs were propagated on NIH 3T3 cells. eGFP-expressing murid herpesvirus 4 (MuHV-4) (30), floxed color-switching MuHV-4 (MHV-RG) (31), and herpes simplex virus 1 (HSV-1) (32) were grown in BHK-21 cells. Infected cell cultures were cleared of cell debris by low-speed centrifugation (500 ϫ g, 10 min).…”

Section: Glmentioning

confidence: 99%

Alveolar Macrophages Are a Prominent but Nonessential Target for Murine Cytomegalovirus Infecting the Lungs

Farrell

Lawler

Oliveira

et al. 2016

Self Cite

H erpesviruses are among the most prevalent of all mammalian pathogens. Many cause lung disease (1-5), making the lung an important site of infection. Human cytomegalovirus (HCMV) causes interstitial pneumonitis in immunocompromised patients (5). While HCMV could potentially reach the lungs via circulating monocytes (6), viral lytic antigen expression in alveolar epithelial cells (AECs) (7-9) and alveolar macrophage (AM) infection (10) suggest entry by inhalation.Sporadic transmission and late clinical presentation make early HCMV infection hard to analyze. However, the relatedness between cytomegaloviruses (CMVs) and their hosts implies that CMV parasitism preceded the speciation of most mammals (11), and peaks of viral diversity in genes engaging the immune functions of diverse hosts suggest that coevolution has operated since to conserve a parasitic status quo. Therefore, nonhuman CMVs can help us to understand how HCMV works. The preeminence of mice as experimental models of mammalian cell biology gives murine CMV (MCMV) particular value in this regard. It causes an interstitial pneumonitis after intranasal (i.n.) inoculation, infecting epithelial and mononuclear cells (12). Thus, it reproduces at least some features of HCMV lung infection.Which lung cells CMVs infect first is unknown. The ciliated upper airways capture large inhaled particles (diameter, Ͼ5 m), but submicron-sized particles, such as viruses, can reach the lung alveoli (13). Here, type 1 alveolar epithelial cells (AEC1s) provide Ͼ90% of the accessible surface, their abundant type 2 progenitors (AEC2s) produce surfactant, and AMs patrol the airspaces for inhaled pathogens. In neonatal mice, i.n. inoculated MCMV infects AMs and AEC2s (14). Infection was reduced when AMs were depleted with liposomal clodronate or when MCMV lacked m129 (15). The m131/m129 MCMV chemokine homolog (designated MCK2) attracts macrophages (16) and alters viral tropism to promote macrophage infection (17). Thus, it was concluded that AMs provide an acutely productive gateway into the lungs. However, MCK2-negative (MCK2 Ϫ ) MCMV given intra-

“…inoculation, it reaches B cells first in the superficial cervical lymph nodes (SCLN). It reaches the NALT only via systemic dissemination (18).…”

mentioning

confidence: 99%

B Cell Response to Herpesvirus Infection of the Olfactory Neuroepithelium

Tan

Stevenson

2014

Self Cite

Viruses commonly infect the respiratory tract. Analyses of host defense have focused on the lungs and the respiratory epithelium. Spontaneously inhaled murid herpesvirus 4 (MuHV-4) and herpes simplex virus 1 (HSV-1) instead infect the olfactory epithelium, where neuronal cilia are exposed to environmental antigens and provide a route across the epithelial mucus. We used MuHV-4 to define how B cells respond to virus replication in this less well-characterized site. Olfactory infection elicited generally weaker acute responses than lung infection, particularly in the spleen, reflecting slower viral replication and spread. Few virus-specific antibody-forming cells (AFCs) were found in the nasal-associated lymphoid tissue (NALT), a prominent response site for respiratory epithelial infection. Instead, they appeared first in the superficial cervical lymph nodes. The focus of the AFC response then moved to the spleen, matching the geography of virus dissemination. Little virus-specific IgA response was detected until later in the bone marrow. Neuroepithelial HSV-1 infection also elicited no significant AFC response in the NALT and a weak IgA response. Thus, olfactory herpesvirus infection differed immunologically from an infection of the adjacent respiratory epithelium. Poor IgA induction may help herpesviruses to transmit via long-term mucosal shedding. IMPORTANCEHerpesviruses are widespread, persistent pathogens against which vaccines have had limited success. We need to understand better how they interact with host immunity. MuHV-4 and HSV-1 inhaled by alert mice infect the olfactory neuroepithelium, suggesting that this is a natural entry route. Its immunology is almost completely unknown. The antibody response to neuroepithelial herpesvirus infection started in the cervical lymph nodes, and unlike respiratory influenza virus infection, did not significantly involve the nasal-associated lymphoid tissue. MuHV-4 and HSV-1 infections also elicited little virus-specific IgA. Therefore, vaccine-induced IgA might provide a defense that herpesviruses are ill-equipped to meet.