Date Published: March 7, 2019
Publisher: Public Library of Science
Author(s): Sebastian Reuter, Niels A. W. Lemmermann, Joachim Maxeiner, Jürgen Podlech, Hendrik Beckert, Kirsten Freitag, Daniel Teschner, Frederic Ries, Christian Taube, Roland Buhl, Matthias J. Reddehase, Rafaela Holtappels, Christopher M. Snyder.
Despite a broad cell-type tropism, cytomegalovirus (CMV) is an evidentially pulmonary pathogen. Predilection for the lungs is of medical relevance in immunocompromised recipients of hematopoietic cell transplantation, in whom interstitial CMV pneumonia is a frequent and, if left untreated, fatal clinical manifestation of human CMV infection. A conceivable contribution of CMV to airway diseases of other etiology is an issue that so far attracted little medical attention. As the route of primary CMV infection upon host-to-host transmission in early childhood involves airway mucosa, coincidence of CMV airway infection and exposure to airborne environmental antigens is almost unavoidable. For investigating possible consequences of such a coincidence, we established a mouse model of airway co-exposure to CMV and ovalbumin (OVA) representing a protein antigen of an inherently low allergenic potential. Accordingly, intratracheal OVA exposure alone failed to sensitize for allergic airway disease (AAD) upon OVA aerosol challenge. In contrast, airway infection at the time of OVA sensitization predisposed for AAD that was characterized by airway inflammation, IgE secretion, thickening of airway epithelia, and goblet cell hyperplasia. This AAD histopathology was associated with a T helper type 2 (Th2) transcription profile in the lungs, including IL-4, IL-5, IL-9, and IL-25, known inducers of Th2-driven AAD. These symptoms were all prevented by a pre-challenge depletion of CD4+ T cells, but not of CD8+ T cells. As to the underlying mechanism, murine CMV activated migratory CD11b+ as well as CD103+ conventional dendritic cells (cDCs), which have been associated with Th2 cytokine-driven AAD and with antigen cross-presentation, respectively. This resulted in an enhanced OVA uptake and recruitment of the OVA-laden cDCs selectively to the draining tracheal lymph nodes for antigen presentation. We thus propose that CMV, through activation of migratory cDCs in the airway mucosa, can enhance the allergenic potential of otherwise poorly allergenic environmental protein antigens.
It is common knowledge in the allergy field that viral respiratory infections and allergic airway diseases (AADs), for instance allergic asthma, can interdepend [1,2]. In principle, mutual interference may aggravate or dampen either of these medical entities. While few publications reported on protective effects of viral infections on the development of asthma [3–5], the majority of studies revealed an exacerbation of asthma by viral respiratory diseases (for reviews see [2,6–11]). On the other hand, damage of the asthmatic lung epithelium can increase the susceptibility to viral infections . Allergic asthma and respiratory viral infections both can affect the physical and functional integrity of the airway epithelium and can thereby destroy its barrier function (reviewed in ). This in turn facilitates the penetration of allergens as well as the invasion of pathogens . In addition, expression of specific immune response genes in lung epithelial cells can be modulated by allergens and by viruses , and there exists evidence to propose a cytokine-based interference between allergic reactions and the antiviral immune response (for an overview see ). Overall, the pathophysiological interactions between respiratory virus infections and allergic airway diseases are manifold and rather complicated, and are not yet fully understood.
Host-to-host transmission of hCMV mostly takes place in early childhood during intimate social contacts of the child with family members or peers who shed the virus with saliva. Local mucosal infection can spread to airway mucosa, where virus and inhaled environmental antigens can meet at airway mucosa-resident DCs capable to migrate upon activation. It was the aim of our study to model this epidemiologically realistic situation for investigating a putative contribution of primary CMV airway infection to sensitization by antigens/allergens that predispose the child for AADs, including asthma. The question is difficult to address by clinical investigation, because primary CMV airway infection in early childhood is usually not diagnosed, so that a link between CMV and AAD years later in life is not obvious to be considered. The here presented data from a mouse model predict that CMV airway infection at the time of exposure to inhaled antigens/allergens can indeed enhance allergenic sensitization that predisposes for AAD. Importantly, the model shows that even a protein antigen that has low-to-no allergenic potential on its own can sensitize for AAD when CMV activates airway mucosa-resident DCs for more efficient antigen uptake. Such a mechanism is medically relevant as it significantly broadens the spectrum of potential environmental inducers of AAD.