Coincident airway exposure to low-potency allergen and cytomegalovirus sensitizes for allergic airway disease by viral activation of migratory dendritic cells

Abstract

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.

Allergen-Immuntherapie in der aktuellen Covid-19-Pandemiea, b, c

“…Es konnte zudem gezeigt werden, dass Zytomegalieviren (CMV) das allergene Potenzial von ansonsten schwach allergenen Umweltallergenen in einem Atemwegsepithel-Mausmodell bei Koexposition gegenüber CMV und Ovalbumin (OVA) verstärken [20].…”

Adverse immunological imprinting by cytomegalovirus sensitizing for allergic airway disease

“…In the model (Fig. 1, top and [17]), immunocompetent C57BL/6 mice were simultaneously exposed via the airways to mCMV and to purified ovalbumin (OVA). OVA was chosen to represent a protein antigen that has low allergenic potential on its own and fails to sensitize for AAD.…”

“…Based on the data by Reuter et al [17], Fig. 2 provides a graphical summary that illustrates the mechanism by which mCMV imprints the immune system for AAD immunopathology.…”

“…In essence, the work by Reuter and colleagues [17] has shown that the key event in sensitization for AAD is the efficient uptake and processing of an inhaled antigen by migratory DC that localize to the airway mucosa as sentinels. Classical allergens and most pathogens have the intrinsic property to activate DC, whereas inhaled environmental protein antigens do not, and are thus ignored by the sentinels.…”

“…Mouse models, provided they are reasonably designed to meet a clinical correlate, have proven predictive value for human disease [16]. As airway exposure to environmental antigens at the time of primary airway infection after hCMV transmission is a realistic scenario of medical interest, recent work modeled this scenario in the mouse with the aim to investigate a possible virus-allergen interplay [17].…”