All authors approved the final manuscript.”
“Background Nontypeable Haemophilus influenzae (NTHi) is a Gram-negative organism that is both a common commensal of the upper respiratory tract as well as a significant cause of respiratory tract infections in humans. NTHi is the second most common cause of acute otitis media after Streptococcus pneumoniae and, in many studies, is the most common cause of recurrent otitis media based on cultures of middle ear fluids obtained by tympanocentesis Selleckchem MLN4924 . Recurrent otitis media is associated with pain, the need for insertion of tympanostomy tubes under general anesthesia, p38 MAPK signaling pathway conductive hearing
impairment, and delayed speech and language development . Currently, otitis media is commonly treated with antibiotics, among which amoxicillin is the consensus recommendation for the initial
therapy [3, 4]. But approximately 20–35% of NTHi strains, depending on geographic location, produce β-lactamase and these strains are resistant to amoxicillin . Moreover, there is currently no licensed vaccine available to prevent NTHi infections. Thus, illuminating the molecular mechanisms of NTHi infections could lead to the development of novel strategies to improve prophylaxis and treatment of otitis media. Adhesin molecules on the surface of NTHi are shown to bind GS-1101 in vitro to respiratory tract target cells and activate these cells to induce inflammation [5, 6]. NTHi also penetrates into human respiratory tract cells (epithelial cells and macrophages) and the interstitium to cause nasopharyngeal colonization and respiratory infection [7–10]. Biofilms of NTHi found in middle ears are postulated to be responsible for the resistance to clearance by host immune responses and antibiotic treatments, therefore resulting in recurrent otitis media [5, 6, 11, 12]. However, there is controversy Reverse transcriptase whether the reported biofilm is an outcome of infectious interactions between the host
and NTHi or a programmed phenotype of NTHi virulence . Although these observations have advanced our understanding, much of the pathogenesis of NTHi-induced otitis media, especially recurrent otitis media, is largely unknown. Toxin-antitoxin (TA) systems are small genetic modules comprised of two components, a stable toxin and its labile antitoxin. TA systems in prokaryotic genomes are classified into 3 types, based on the antitoxin nature and mode of action. While toxins are always proteins, antitoxins are either RNAs (types I and III) or proteins (type II) . Several common families of type II modules have been identified on the chromosomes of bacteria and archaea: relBE, higBA, mazEF, ccdAB, vapBC, parDE, phd–doc, ζε, hipBA, and yoeB–yefM. Type II TA systems are thought to be part of the mobilome and to move from one genome to another through horizontal gene transfer [16, 17].