Murine alveolar macrophages limit replication of vaccinia virus

Rivera, Rachel; Hutchens, Martha; Luker, Kathryn E.; Sonstein, Joanne; Curtis, Jeffrey L.; Luker, Gary D.

doi:10.1016/j.virol.2007.01.033

Cited by 33 publications

(33 citation statements)

References 25 publications

(31 reference statements)

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“…Alveolar macrophages (AMs) are strategically situated as a first lung defense against respiratory pathogens and therefore play a central role in innate host defense and in the maintenance of immunological homeostasis (6). They are capable of sensing pathogen-associated molecular patterns and of initiating innate and adaptive immune responses against invading pathogens.…”

Section: Clinical Relevancementioning

confidence: 99%

Alveolar Macrophages Contribute to the Pathogenesis of Human Metapneumovirus Infection while Protecting against Respiratory Syncytial Virus Infection

Kolli¹,

Gupta²,

Sbrana³

et al. 2014

Am J Respir Cell Mol Biol

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Human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) are leading causes of upper and lower respiratory tract infections in young children and among elderly and immunocompromised patients. The pathogenesis of hMPVinduced lung disease is poorly understood. The lung macrophage population consists of alveolar macrophages (AMs) residing at the luminal surface of alveoli and interstitial macrophages present within the parenchymal lung interstitium. The involvement of AMs in innate immune responses to virus infections remains elusive. In this study, BALB/c mice depleted of AMs by intranasal instillation of dichloromethylene bisphosphonate (L-CL 2 MBP) liposomes were examined for disease, lung inflammation, and viral replication after infection with hMPV or RSV. hMPV-infected mice lacking AMs exhibited improved disease in terms of body weight loss, lung inflammation, airway obstruction, and hyperresponsiveness compared with AM-competent mice. AM depletion was associated with significantly reduced hMPV titers in the lungs, suggesting that hMPV required AMs for early entry and replication in the lung. In contrast, AM depletion in the context of RSV infection was characterized by an increase in viral replication, worsened disease, and inflammation, with increased airway neutrophils and inflammatory dendritic cells. Overall, lack of AMs resulted in a broad-spectrum disruption in type I IFN and certain inflammatory cytokine production, including TNF and IL-6, while causing a virus-specific alteration in the profile of several immunomodulatory cytokines, chemokines, and growth factors. Our study demonstrates that AMs have distinct roles in the context of human infections caused by members of the Paramyxoviridae family.

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Section: Clinical Relevancementioning

confidence: 99%

Alveolar Macrophages Contribute to the Pathogenesis of Human Metapneumovirus Infection while Protecting against Respiratory Syncytial Virus Infection

Kolli¹,

Gupta²,

Sbrana³

et al. 2014

Am J Respir Cell Mol Biol

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“…BAL was performed as described previously (20). The first milliliter of lavage fluid was used for analyses of total protein and cytokines.…”

Section: Bronchoalveolar Lavage (Bal)mentioning

confidence: 99%

TLR3 Increases Disease Morbidity and Mortality from Vaccinia Infection

Hutchens

Luker²,

Sottile³

et al. 2008

The Journal of Immunology

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Innate immunity is required for effective control of poxvirus infections, but cellular receptors that initiate the host response to these DNA viruses remain poorly defined. Given this information and the fact that functions of TLRs in immunity to DNA viruses remain controversial, we investigated effects of TLR3 on pathogenesis of vaccinia virus, a prototype poxvirus. We used a recombinant strain Western Reserve vaccinia virus that expresses firefly luciferase to infect wild-type C57BL/6 and TLR3−/− mice through intranasal inoculation. Bioluminescence imaging showed that TLR3−/− mice had substantially lower viral replication in the respiratory tract and diminished dissemination of virus to abdominal organs. Mice lacking TLR3 had reduced disease morbidity, as measured by decreased weight loss and hypothermia after infection. Importantly, TLR3−/− mice also had improved survival relative to wild-type mice. Infected TLR3−/− mice had significantly reduced lung inflammation and recruitment of leukocytes to the lung. Mice lacking TLR3 also had lower levels of inflammatory cytokines, including IL-6, MCP-1, and TNF-α in serum and/or bronchoalveolar lavage fluid, but levels of IFN-β did not differ between genotypes of mice. To our knowledge, our findings show for the first time that interactions between TLR3 and vaccinia increase viral replication and contribute to detrimental effects of the host immune response to poxviruses.

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“…After inhalation, VACV-WR infects multiple cell types in the lung, including alveolar macrophages (10), dendritic cells (DCs) (11), and bronchiolar and alveolar epithelial cells (12). Over the next few days, the virus replicates exponentially in the lung, resulting in perivascular and peribronchial inflammation, hypertrophy and hyperplasia of epithelial cells, and diffuse alveolar damage (9).…”

mentioning

confidence: 99%

“…In general, it is believed that recovery from a respiratory VACV infection requires a tightly coordinated response by both the innate and adaptive immune systems. In this regard, a limited number of studies have shown that pattern recognition receptors (13)(14)(15)(16), alveolar macrophages (10), and dendritic cells direct the early response to VACV (11,17,18). As the adaptive immune response develops, virus-specific CD8 T cells play a vital role in restricting lung pathology and virus dissemination to visceral tissues and are necessary for complete clearance of virus and protection against death (19).…”

mentioning

confidence: 99%

Natural Killer Cells and Innate Interferon Gamma Participate in the Host Defense against Respiratory Vaccinia Virus Infection

Abboud

Tahiliani

Desai

et al. 2016

J Virol

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In establishing a respiratory infection, vaccinia virus (VACV) initially replicates in airway epithelial cells before spreading to secondary sites of infection, mainly the draining lymph nodes, spleen, gastrointestinal tract, and reproductive organs. We recently reported that interferon gamma (IFN-␥) produced by CD8 T cells ultimately controls this disseminated infection, but the relative contribution of IFN-␥ early in infection is unknown. Investigating the role of innate immune cells, we found that the frequency of natural killer (NK) cells in the lung increased dramatically between days 1 and 4 postinfection with VACV. Lung NK cells displayed an activated cell surface phenotype and were the primary source of IFN-␥ prior to the arrival of CD8 T cells. In the presence of an intact CD8 T cell compartment, depletion of NK cells resulted in increased lung viral load at the time of peak disease severity but had no effect on eventual viral clearance, disease symptoms, or survival. In sharp contrast, RAG ؊/؊ mice devoid of T cells failed to control VACV and succumbed to infection despite a marked increase in NK cells in the lung. Supporting an innate immune role for NK cell-derived IFN-␥, we found that NK cell-depleted or IFN-␥-depleted RAG ؊/؊ mice displayed increased lung VACV titers and dissemination to ovaries and a significantly shorter mean time to death compared to untreated NK cell-competent RAG ؊/؊ controls. Together, these findings demonstrate a role for IFN-␥ in aspects of both the innate and adaptive immune response to VACV and highlight the importance of NK cells in T cell-independent control of VACV in the respiratory tract. IMPORTANCEHerein, we provide the first systematic evaluation of natural killer (NK) cell function in the lung after infection with vaccinia virus, a member of the Poxviridae family. The respiratory tract is an important mucosal site for entry of many human pathogens, including poxviruses, but precisely how our immune system defends the lung against these invaders remains unclear. Natural killer cells are a type of cytotoxic lymphocyte and part of our innate immune system. In recent years, NK cells have received increasing levels of attention following the discovery that different tissues contain specific subsets of NK cells with distinctive phenotypes and function. They are abundant in the lung, but their role in defense against respiratory viruses is poorly understood. What this study demonstrates is that NK cells are recruited, activated, and contribute to protection of the lung during a severe respiratory infection with vaccinia virus.

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Murine alveolar macrophages limit replication of vaccinia virus

Cited by 33 publications

References 25 publications

Alveolar Macrophages Contribute to the Pathogenesis of Human Metapneumovirus Infection while Protecting against Respiratory Syncytial Virus Infection

Alveolar Macrophages Contribute to the Pathogenesis of Human Metapneumovirus Infection while Protecting against Respiratory Syncytial Virus Infection

TLR3 Increases Disease Morbidity and Mortality from Vaccinia Infection

Natural Killer Cells and Innate Interferon Gamma Participate in the Host Defense against Respiratory Vaccinia Virus Infection

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