Beta-lactam antibiotics modulate T-cell functions and gene expression via covalent binding to cellular albumin

Abstract

Recent work has suggested that beta-lactam antibiotics might directly affect eukaryotic cellular functions. Here, we studied the effects of commonly used beta-lactam antibiotics on rodent and human T cells in vitro and in vivo on T-cell–mediated experimental autoimmune diseases. We now report that experimental autoimmune encephalomyelitis and adjuvant arthritis were significantly more severe in rats treated with cefuroxime and other beta-lactams. T cells appeared to mediate the effect: an anti-myelin basic protein T-cell line treated with cefuroxime or penicillin was more encephalitogenic in adoptive transfer experiments. The beta-lactam ampicillin, in contrast to cefuroxime and penicillin, did not enhance encephalomyelitis, but did inhibit the autoimmune diabetes developing spontaneously in nonobese diabetic mice. Gene expression analysis of human peripheral blood T cells showed that numerous genes associated with T helper 2 (Th2) and T regulatory (Treg) differentiation were down-regulated in T cells stimulated in the presence of cefuroxime; these genes were up-regulated in the presence of ampicillin. The T-cell protein that covalently bound beta-lactam antibiotics was found to be albumin. Human and rodent T cells expressed albumin mRNA and protein, and penicillin-modified albumin was taken up by rat T cells, leading to enhanced encephalitogenicity. Thus, beta-lactam antibiotics in wide clinical use have marked effects on T-cell behavior; beta-lactam antibiotics can function as immunomodulators, apparently through covalent binding to albumin.

Environmental control of autoimmune inflammation in the central nervous system

“…While the first report from 2011 was verified and germ free mice showed either complete resistance or attenuation of EAE in several experimental paradigms 46–48 , using antibiotic cocktails to deplete gut microbiota has provided controversial results. Even though most of the antibiotic administration studies have shown an amelioration of EAE pointing to a disease promoting effect of gut bacteria 49–51 , experimental evidence suggests that certain bacterial strains have a beneficial effect on EAE development and protect from exacerbated disease, as shown in treatment experiments using the macrolide antibiotics clarithromycine and azithromycin or the cephalosporine cefuroxime 52,53 .…”

Biotic acts of antibiotics

“…Interestingly, ceftriaxone has had no impact on the EAAT2 protein expression levels in several brain areas as well as on the glutamate uptake rate suggesting that in this model the positive effects of the antibiotic are not mediated through the modulation of glutamate concentration. Moreover, it seems that even the individual antibiotics within the β-lactam group may display differential immunomodulatory properties (Mor and Cohen, 2013). This mechanism operates via covalent binding of various β-lactams to cellular albumin and subsequent modulation of T cell function and gene expression.…”

Isoniazid‐induced control of Mycobacterium tuberculosis by primary human cells requires interleukin‐1 receptor and tumor necrosis factor

“…In this context, it is thought that some antibiotic compounds may directly stimulate the host immune system [16,17]. The current TB chemotherapy contains four first-line antibiotics namely, rifampicin, ethambutol, pyrazinamide and isoniazid.…”

“…In addition to antibiotics, which are major therapeutic tools to promote further suppression of mycobacterial growth [13], host-targeted interventions have also been proposed as novel approaches to enhance control of TB [14,15]. In this context, it is thought that some antibiotic compounds may directly stimulate the host immune system [16,17] [27]. In that study, the authors have demonstrated a role for host autophagy as an essential requirement to the bactericidal activity of INH in H37Rv-infected murine macrophages.…”