tetracycline and Orthomyxoviridae-Infections

Mitohormesis defines the increase in fitness mediated by adaptive responses to mild mitochondrial stress. Tetracyclines inhibit not only bacterial but also mitochondrial translation, thus imposing a low level of mitochondrial stress on eukaryotic cells. We demonstrate in cell and germ-free mouse models that tetracyclines induce a mild adaptive mitochondrial stress response (MSR), involving both the ATF4-mediated integrative stress response and type I interferon (IFN) signaling. To overcome the interferences of tetracyclines with the host microbiome, we identify tetracycline derivatives that have minimal antimicrobial activity, yet retain full capacity to induce the MSR, such as the lead compound, 9-tert-butyl doxycycline (9-TB). The MSR induced by doxycycline (Dox) and 9-TB improves survival and disease tolerance against lethal influenza virus (IFV) infection when given preventively. 9-TB, unlike Dox, did not affect the gut microbiome and also showed encouraging results against IFV when given in a therapeutic setting. Tolerance to IFV infection is associated with the induction of genes involved in lung epithelial cell and cilia function, and with downregulation of inflammatory and immune gene sets in lungs, liver, and kidneys. Mitohormesis induced by non-antimicrobial tetracyclines and the ensuing IFN response may dampen excessive inflammation and tissue damage during viral infections, opening innovative therapeutic avenues.

Topics: Animals; Anti-Bacterial Agents; Doxycycline; Humans; Influenza, Human; Mice; Orthomyxoviridae Infections; Tetracycline; Tetracyclines

Because of the practical value of the study of peculiar properties of antinfluenza immunity under conditions of the use of tetracycline, streptomycin and penicillin, the experiments were performed on albino mice and rats. The studies showed that the antibiotics inhibited the intensity of production of specific antibodies, i.e. antihemagglutinines and virus neutralizing antibodies in the process of antiinfluenza immunization of the animals which must be connected with changes in the cells of the immunoreactive system, suppression of the activity of the metabolic processes.

Topics: Administration, Intranasal; Animals; Anti-Bacterial Agents; Antibodies, Viral; Antibody Formation; Antigens, Viral; Chick Embryo; Depression, Chemical; Hemagglutination Inhibition Tests; Immunity; Immunization; Injections, Intramuscular; Mice; Neutralization Tests; Orthomyxoviridae Infections; Penicillins; Rats; Streptomycin; Tetracycline; Time Factors

Topics: Acute Disease; Adult; Aged; Child; gamma-Globulins; Humans; Influenza Vaccines; Influenza, Human; Orthomyxoviridae Infections; Respiratory Tract Infections; Sulfamethoxazole; Tetracycline; Trimethoprim