Macrophage Impairment Underlies Airway Occlusion in Primary Respiratory Syncytial Virus Bronchiolitis

Abstract

Although respiratory syncytial virus (RSV) infection is the most important cause of bronchiolitis in infants, the pathogenesis of RSV disease is poorly described. We studied histopathologic changes in a panel of lung tissue specimens obtained from infants with fatal cases of primary RSV infection. In these tissues, airway occlusion with accumulations of infected, apoptotic cellular debris and serum protein was consistently observed. Similar observations were found after RSV infection in New Zealand black (NZB) mice, which have constitutive deficiencies in macrophage function, but not in BALB/c mice. A deficiency in the number of alveolar macrophages in NZB mice appears to be central to enhanced disease, because depletion of alveolar macrophages in BALB/c mice before RSV exposure resulted in airway occlusion. In mice with insufficient numbers of macrophages, RSV infection yielded an increased viral load and enhanced expression of type I interferon-associated genes at the height of disease. Together, our data suggest that innate, rather than adaptive, immune responses are critical determinants of the severity of RSV bronchiolitis.

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

“…The relevance of these data is further supported by the observation that, in contrast to hMPV depletion of AMs before RSV infection resulted in an increase in viral replication and overall worsening of disease parameters and lung pathology. Our results in the RSV model are in agreement with reports by others (7)(8)(9) and are consistent in general with studies of other respiratory viral pathogens, including influenza virus, suggesting that AMs are indeed necessary for viral clearance and control of disease (16). The precise mechanism(s) by which AMs control viral infections is unclear but may include production of type I IFN, nitric oxide, and the phagocytosis of virus-infected cells by AMs (27).…”

“…AMs are also a primary source of inflammatory and immunomodulatory cytokines in lungs, and in general their depletion has been shown to result in an impaired host response against viral and bacterial pathogens (7,8). For example, mice that are depleted of AMs or have constitutive deficiencies in macrophage function show enhanced RSV replication and viral-induced airway occlusion, respectively (7)(8)(9), suggesting a protective role of AMs in the context of human paramyxovirus infections.…”

Infant baboons infected with respiratory syncytial virus develop clinical and pathological changes that parallel those of human infants

“…Macrophages became the predominant cell type present from days 4 to 8, a time when illness was most severe. This may suggest that macrophages are the most important cell responsible for eradicating virus and clearing debris from the airway, as has been demonstrated in mouse models of RSV infection (29). Alternatively, it may mean that exaggerated macrophage responses somehow contribute to illness.…”

Animal models of human respiratory syncytial virus disease

“…As stated above, there are only a few published histopathology studies of acute hRSV disease available for general consideration (2,62,96,116,117). In the rare fatal cases of bronchiolitis, small airway entrapment by dense plugs composed of mucus, fibrin, and cellular debris from leukocytes and dead bronchial epithelial cells has been observed (2,62,96,116). Submucosal edema and peribronchiolar infiltrates composed of mixed mono-and polymorphonuclear cells (PMNs) further contribute to the small-airway narrowing and occlusion.…”