Interleukin-4Ra Blockade by Dupilumab Decreases Staphylococcus Colonization and Increases Microbial Diversity in CRSwNP

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is an important clinical problem and is associated with profound unmet medical needs given the absence - until recently - of adequate medical therapies. It has an estimated prevalence of 2-4% in the USA and Europe but also has disproportionate burden on quality of life and economic burden.

CRSwNPs is predominantly (in 62-85% of patients) a type 2 (T2) disease, as demonstrated by an IL-4high, IL-5high, IL-13high cytokine signature and prominent infiltration with eosinophils, basophils, and newly recruited mast cells. Another characteristic feature of CRSwNPs is the colonization of the sinonasal space with Staphylococcus aureus (Staph). Staph comprises <10% of the bacterial biomass of the healthy nose but infections with this pathogen is observed in the majority of CRSwNP patients and especially in those with asthma comorbidity or AERD.

Evidence exists for an upregulatory vicious circle involving type 2 inflammation promoting an immune deficient state with reduced innate immune responsiveness to staph, leading to colonization/infection with staph and then with the staph producing exotoxins and other pathogen-associated molecular patterns (PAMPs) that promote and exacerbate the T2high state. A central endogenous immune defense to protect against colonization and infection with staph consists of innate immune-derived anti-microbial proteins (AMPs). There are two major families of AMPs, the defensins and the cathelicidins that together comprise >2000 proteins. These cationic proteins provide immune defenses against a range of pathogens. Downregulation of the ß-defensins (BD)-2 and BD-3 and cathelicidin LL-37 is particularly relevant to atopic dermatitis (AD) and underlies the particular susceptibility of AD skin to colonization and infection with staph. Thus, in AD staph can comprise up to 90% of the bacterial species present on the skin. These AMPs are predominantly expressed in epithelial cells including of the skin but are also expressed by airway epithelial cells (AECs). Sinonasal AECs produce all the ß-defensins (BD1-4) and BD1-3 expression is reduced in allergic inflammatory diseases of the airway. In addition to AMPs shared with the dermis, another important AMP, S100A7 (psoriasin) is also uniquely reduced in CRS.

This diminished expression of ß-defensins and cathelicidin in AD has been ascribed to overproduction of IL-4/IL-13. Inhibition of AMP expression in upper airway allergic disease has also been ascribed to these cytokines. In addition to inhibiting its production, IL-4/IL-13 also block the mobilization of BD-3 to the surface of staph. T2 cytokines further promote staph infection in AD by enhancing binding of these pathogens to atopic skin. Finally, IL-4/IL-13 may further enhance susceptibility to infection through their adverse impact on tight junction barrier function, thereby promoting microinvasive disease and access of PAMPs to submucosal targets.

The final component of the pro-inflammatory vicious circle is the capacity of Staph-derived enterotoxins to feedback to enhance production of T2-associated cytokines, thereby further exacerbating eosinophilic inflammation and the reduced innate immune defense against pathogens. This enhancement of the T2 signature has traditionally been ascribed to the production of superantigens (and antigens) by staph that engage Th2 effector cells residing in the sinuses via their T cell receptor and stimulates their further activation and cytokine secretion. However, staph-derived PAMPs including lipoteichoic acid and staph enterotoxin B (SEB) can also induce secretion of T2-promoting cytokines such as IL-33 and TSLP by engagement of toll-like receptor (TLR)2 and other pathogen recognition receptors (PRRs) on AECs.

In summary CRSwNPs frequently comprises a state in which staph-derived PAMPs exacerbate an already established T2high inflammatory condition, T2-derived cytokines but in particular IL-4 and IL-13 interact with AECs to reduce AMP production, and reduced expression of AMPs promotes the colonization and further infection with staph.

This pathogenic mechanism is now unambiguously established in atopic dermatitis. This was demonstrated via the ability of blockade of IL-4/IL-13 via administration of anti-IL-4R to decrease Staphylococcus aureus colonization and increase microbial diversity in atopic dermatitis - an effect that strongly correlated with clinical benefit. The investigators propose that a similar molecular mechanism for dupilumab will be observed in CRSwNPs.