Innate Immunity Induced by the Major Allergen Alt a 1 From the Fungus Alternaria Is Dependent Upon Toll-Like Receptors 2/4 in Human Lung Epithelial Cells

Abstract

Allergens are molecules that elicit a hypersensitive inflammatory response in sensitized individuals and are derived from a variety of sources. Alt a 1 is the most clinically important secreted allergen of the ubiquitous fungus, Alternaria. It has been shown to be a major allergen causing IgE-mediated allergic response in the vast majority of Alternaria-sensitized individuals. However, no studies have been conducted in regards to the innate immune eliciting activities of this clinically relevant protein. In this study, recombinant Alt a 1 was produced, purified, labeled, and incubated with BEAS-2B, NHBE, and DHBE human lung epithelial cells. Alt a 1 elicited strong induction of IL-8, MCP-1, and Gro-a/b/g. Using gene-specific siRNAs, blocking antibodies, and chemical inhibitors such as LPS-RS, it was determined that Alt a 1-induced immune responses were dependent upon toll-like receptors (TLRs) 2 and 4, and the adaptor proteins MYD88 and TIRAP. Studies utilizing human embryonic kidney cells engineered to express single receptors on the cell surface such as TLRs, further confirmed that Alt a 1-induced innate immunity is dependent upon TLR4 and to a lesser extent TLR2.

Alternariol as virulence and colonization factor of Alternaria alternata during plant infection

“…The relation of such severe diseases to the consumption of intoxicated food are usually difficult, but likely the treatment of the diseases is very costly. In addition to A. alternata being a potent producer of secondary metabolites, it is known as one of the major causes of fungal allergies in human and animals (Breitenbach and Simon‐Nobbe, ; Babiceanu et al , ; Hayes et al , ).…”

Effects of Essential Oil Citral on the Growth, Mycotoxin Biosynthesis and Transcriptomic Profile of Alternaria alternata

“…Besides, they possess cytotoxicity as well as reproductive and developmental toxicity [4]. In addition, A. alternata is regarded as a critically common cause of allergic rhinitis and atopic asthma owing to the production of Alternaria allergens, such as the major allergen, Alt a 1 [8,9].…”

Competing Bioaerosols May Influence the Seasonality of Influenza-Like Illnesses, including COVID-19. The Chicago Experience

“…The similarity of the proposed mold spore dose dependencies for abatement of flu and COVID-19 suggests a shared receptor. Although much attention has been given to angiotensin-converting enzyme 2 (ACE-2) and its role in COVID-19 [ 12 , 13 ], there are compelling reasons to believe TLR4, which binds the SARS-CoV-2 spike protein with greater affinity than does ACE-2 [ 49 ], is also operative: 1) TLR4 is implicated in the inflammatory response triggered by sharply seasonal respiratory viruses [ 16 , 17 , 18 ], 2) TLR4 has a significant role in innate defense against multiple species of fungi [ 19 , 20 ] and polymorphisms in TLR4 are associated with invasive fungal disease [ 50 , 51 ], 3) COVID-19 prognosis correlates with radiographic involvement of alveolar spaces [ 21 , 22 ], the epithelial surfaces of which are poor in ACE-2 [ 52 , 53 ] but rich in TLR4 [ 23 ], (4) inflammation of the sort associated with acute lung injury is mediated by TLR4 [ 14 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ], (5) age-dependent hyper-responsiveness of TLR4 [ 24 ], especially in the context of interactions with TLR5 [ 25 , 26 ], can account for the age-dependent severity of COVID-19 and (6) fibrino(gen) D-dimers are markedly elevated in persons with severe COVID-19 [ 28 ]. That TLR4 may be involved in the processing of bioaerosols is also expected on phylogenetic grounds: the receptor has been retained by some fish that breathe air but lost by those that do not [ 63 ], and the eponymous Toll receptor controls the antifungal response of Drosophila [ 64 ].…”

“…Indeed, such interactions are well described for a number of pollens and mold spores, and there is no reason to believe viruses, despite their smaller size, interact differently. Implicating Toll-like receptors, Toll-like receptor 4 (TLR4) in particular, seems appropriate on phenomenological grounds as well: (1) engagement of TLR 4 can account for the inflammatory signaling characteristic of severe COVID-19 [ 14 , 15 ], (2) TLR4 is intimately involved in the inflammation elicited both by sharply seasonal respiratory viruses and by multiple species of fungi [ 16 , 17 , 18 , 19 , 20 ], (3) COVID-19 prognosis correlates with radiographic involvement of alveoli [ 21 , 22 ], the epithelial cells of which are rich in TLR4 [ 23 ], (4) age-dependent hyper-responsiveness of TLR4 [ 24 ], especially in the context of TLR5 [ 25 , 26 ], can account for the age dependent severity of COVID-19, and (5) fibrinogen D-dimers, composites of TLR4 ligands [ 27 ], are markedly elevated in persons with severe COVID-19 [ 28 ].…”