Autophagy, from the Greek words meaning “self-eating”, is an evolutionarily conserved multistep process preserved amongst all eukaryotes to maintain cellular homeostasis(1). It is an intracellular, catabolic process whereby dysfunctional organelles such as mitochondria and inflammasomes, aggregated or unneeded proteins as well as intracellular bacteria and viruses and their components are degraded(2,3). The entities marked for destruction become surrounded by a double membrane structure called an autophagosome. The autophagosome fuses with a lysosome and the sequestered components are catabolized by lysosomal enzymes(4,5,6). The resulting amino acids, fatty acids, carbohydrates and nucleic acid components are returned to the cytoplasm to provide additional nutrients for various metabolic processes.
Under physiological conditions, autophagy is maintained at a low basal level in most cells(7). Its induction is primarily inhibited by a compound called mammalian inhibitor of rapamycin (mTOR) that senses the availability of nutrients, oxidative stress as well as other deviations from intracellular homeostasis(8,9,10). When non-physiological conditions that increase cellular stress develop mTOR is inhibited and the pathway to autophagy is activated(11). More specifically, the pathway of autophagy is induced by nutrient and oxygen deprivation, decreased levels of growth factors, the presence of a cytotoxic environment, oxidative stress due to defective mitochondria, and intracellular changes induced by infection or malignancy(12,13,14).
In addition to its central role in the clearance of intracellular pathogens autophagy has an additional role in the regulation of both innate and adaptive immunity. Peptides produced by the lysosome-mediated degradation of microorganisms that have been sequestered in autophagosomes combine with major histocompatibility complex molecules and migrate to the cell surface. Their subsequent binding to receptors on the surface of T lymphocytes results in the activation of peptide-specific acquired immunity(15). Activated T cells as well as antibody production by activated B lymphocytes require additional energy and this is provided by activation of autophagy within these immune cells(16). Autophagy also prevents the induction of excessive inflammation that can harm healthy cells. It inhibits the activation of NF?B, the transcription factor that turns on genes coding for pro-inflammatory cyto- kines(13,17). In addition, it down-regulates production of the primary pro-inflammatory cytokine, interleukin (IL)1ß, by sequestering and degrading an intracellular structure called an inflammasome that is responsible for production of biologically active IL-1ß(18,19,20).
The contribution of autophagy in eliminating sexually transmitted viruses and bacteria that infect the female genital tract has received only limited attention. This editorial highlights the role of autophagy in the defense against these infections and the mechanism utilized by sexually transmitted pathogens to circumvent autophagy-mediated destruction. Novel studies are proposed, based on these interactions to facilitate autophagy-mediated destruction of female genital tract pathogens.
The role of interferon (IFN)-? is pivotal in combating chlamydial infections; its introduction eliminates this bacterium(25). IFN-? depletes intracellular tryptophan and iron, induces production of nitric oxide, and activates host autophagy(8,13,26). Recent data have shown that IFN-? induces the fusion of autophagosomes with chlamydial inclusion bodies via a mechanism involving induction of guanylate binding proteins(27).
There remains a still largely unmet need to identify the role of autophagy in a chlamydial genital tract infection. What is the mechanism by which an intracellular chlamydial infection prevents autophagy induction and how can this be reversed? Are women with an inherited or acquired deficit in autophagy induction at increased susceptibility to this infection and its sequelae? Can we identify compounds that can safely induce autophagy and/or IFN-? production in women newly infected with
Recurrent vulvovaginal candidiasis (RVVC) is a frustrating consequence of a
Type I and type 2 herpes simplex virus (HSV) are double stranded DNA viruses that infect the female genital tract. They can cause painful lesions and, in pregnancy, are major inducers of neonatal morbidity and mortality. Their intracellular replication should be inhibited and the virus destroyed by autophagy. However, both HSV 1 and HSV 2 produce a protein, infected cell protein 34.5 (ICP34.5), that inhibits formation of the autophagosome and, thereby, prevents viral elimination(30). Hu- man cytomegalovirus (CMV) produces an analogous protein, TRS1, that also inhibits autophagy in CMV-infected cells(31). Thus, herpesvi- ruses persist within host cells by inhibiting autophagy. The introduction of exogenous agents capable of inducing autophagy in herpesvirus-infected cells appears to be a logical option worthy of evaluation.
HPV, a double stranded DNA virus, is the etiological agent of cervical carcinoma as well as a causative factor for anal cancer and head and neck malignancies(32). HPV infects terminally differentiated epithelial cells in the female genital tract. The induction of autophagy in these infected cells is essential for the production of amino acids needed for HPV replication as well as for the continued survival of the host cell. The HPV E7 protein has been shown to induce autophagy in epithelial cells. Uninfected epithelial cells that have been transfected with the E7 protein undergo autophagy(33).
The inhibition of autophagy in HPV-infected genital tract epithelial cells to limit the consequences of this infection is an attractive but unexplored area of research. Development of protocols to target HPV-infected cells with agents that inhibit autophagy and/or activate mTOR might be useful adjuncts to conventional treat- ments. In addition, contrary to the situation with
HIV is a retrovirus that infects monocytes/macrophages and CD4+ T lymphocytes in the female genital tract. Like herpesviruses, the intracellular replication of HIV should be disrupted by autophagy. However, unlike herpesviruses, HIV uses autophagy to facilitate its replication in monocytes/macrophages. The HIV gag protein binds to an essential autophagy component, LC3, and facilitates the assembly of HIV within autophagosomes(34). A second HIV protein, nef, binds to another autophagy component, Beclin 1, and inhibits the autophagosome from interacting with a lysosome(34). A third HIV protein, tat, prevents IFN-? from inducing autophagy in HIV-infected cells(35). When HIV infects CD4+ T cells the HIV env protein is released into the extracellular milieu where it binds to uninfected CD4+ T cells. This re- sults in the induction of autophagy in these cells and their subsequent destruction by apoptosis(36). This elimination of uninfected T cells down-regulates anti-HIV immunity and facilitates viral persistence.
Thus, HIV has evolved an amazing repertoire of mechanisms that target autophagy. This suggests that autophagy has a major role in HIV biology. However, focusing on the development of mechanisms to promote autophagy to eliminate HIV in infected monocytes/macrophages and to prevent autophagy in uninfected T cells has received scant research attention.
Autophagy is a major mechanism to eliminate microorganisms that reside within the cytoplasm of infected cells and to promote effective anti-microbial immune responses. Microorganisms that successfully invade the female genital tract have evolved mechanisms to prevent their autophagy-mediated destruction, utilize autophagy to promote their survival and/or promote their ability to replicate within host cells. The testing of novel protocols to prevent or reverse the microorganism-directed subversion of autophagy remains an under-appreciated area of research. It is our hope that this editorial will facilitate laboratory investigations that result in development of novel means to combat the initiation, development and consequences of sexually transmitted infections.
Division of Immunology and Infectious Diseases, Department of Obstetrics and Gynecology, Weill Cornell Medicine. E-mail: email@example.com