Thinking outside the box: new strategies for antichlamydial control

Abstract

Future MicrobiologyVol. 7, No. 4 EditorialFree AccessThinking outside the box: new strategies for antichlamydial controlRaphael H ValdiviaRaphael H ValdiviaDepartment of Molecular Genetics & Microbiology & Center for Microbial Pathogenesis, Duke University Medical Center, Durham, NC 27710, USA. Search for more papers by this authorEmail the corresponding author at valdi001@mc.duke.eduPublished Online:23 Mar 2012https://doi.org/10.2217/fmb.12.25AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: anti-infectiveChlamydiatherapyvirulenceChlamydial diseases account for significant morbidity throughout the world. For instance, the healthcare costs linked to complications from infection with the sexually transmitted intracellular bacteria Chlamydia trachomatis exceeds US$4 billion annually in the USA alone [1]. In addition, there is a significant public health burden associated with untreated ocular infections that can lead to trachoma, a blinding disease that affects over 6 million individuals worldwide [1]. Although primary chlamydial infections are readily controlled with a single dose of azithromycin or a short course of doxycycline, reinfections are common. The extent to which these infections occur as a result of re-exposure to the pathogen, reactivation of latent infections or both is not clear. Regardless of the source, the pathology associated with recurrent infections tends to be more severe than the initial exposure, which further increases the risk of costly health complications, such as pelvic inflammatory diseases, ectopic pregnancies and infertility [2].Part of the challenge in developing strategies to contain Chlamydia infections is that the pathogen is widely disseminated in human populations, with a large fraction of infected people remaining asymptomatic or with subclinical symptoms. As a result, aggressive screening programs, especially for high-risk populations such as teenagers and young adults, have been implemented in an attempt to curtail the spread of the pathogen and to decrease the reservoir for infections. Paradoxically, despite these aggressive screening and antibiotic intervention programs, the rate of new C. trachomatis infections continues to increase [3]. Some of the increased rates of infections may reflect more widespread testing performed by primary care providers and family planning centers, as well as the availability of more sensitive tests. However, it has also been proposed that early antibiotic intervention programs may have had the unexpected consequence of decreasing herd immunity by eliminating bottlenecks to Chlamydia transmission through human populations [4].The ideal control strategy for chlamydial diseases would be the development of a protective vaccine. Unfortunately, progress in vaccine development has been limited. Early trachoma vaccine trials in humans with inactivated Chlamydia offered some degree of protection, but enthusiasm for such approaches was tempered by potential hypersensitivity reactions and by the short-lived protection these vaccines afforded [5]. A variety of subunit vaccines have also been tested in experimental animals, but the level of protection has been mixed and immunity is also not long-lived [5]. Based on animal experiments, it is clear that live organisms afford a much greater level of protection than dead ones, with a greater diversity of epitopes displayed on immune cells [6]. Live-attenuated strains of Chlamydia abortus have proven to be partially effective in protecting livestock and in experimental immunization [5], and plasmid-deficient strains can protect nonhuman primates from infection in trachoma infection models [7]. Similarly, Chlamydia muridarum strains without plasmids – a mouse-adapted pathogen – do not display replication defects in vitro, but are attenuated during experimental animal infections, and are impaired for the induction of Toll-like receptor 2-mediated inflammation and upper genital tract pathology [8]. Interestingly, plasmid-encoded factors control the transcription of various chromosomal genes, including putative virulence factors [9]. While virulence defects in plasmid-cured strains are not universal among chlamydial species [10,11], the findings in C. trachomatis and C. muridarum suggest that a ‘right’ attenuated strain, preferably one that is not just defective for some metabolic process but lacking a specific virulence factor, could induce minimal pathology upon initial infection, yet still offer a degree of protection to subsequent infections. In particular, virulence factors that could impede the development of protective immunity may be appealing targets. Indeed, cellular microbiology studies have revealed multiple mechanisms that Chlamydia may employ to globally impair the onset of innate and adaptive immune responses. These include proteases [12] and type III secreted effectors that inhibit various signaling pathways that are important in immunity or that limit the exposure of microbial compounds to pattern recognition receptors [13,14]. As a caveat, it is important to note that many of these candidate ‘immunomodulatory’ molecules were identified in in vitro infection systems. Their relative contribution to infections in vivo remains to be determined.A direct test of the hypothesis that targeting Chlamydia’s immunomodulatory arsenal will result in enhanced immune responses has been hampered by our inability to genetically manipulate the organism or to inhibit the function of specific virulence factors. Fortunately, recent advances in Chlamydia genetics may very well permit the rational construction of strains with defined lesions that can then be tested in animals [15–17].In recent years, there has been increased interest in the development of anti-infective drugs that specifically disarm virulence factors [18]. These compounds could act as novel antimicrobials by preventing host colonization or by impairing the survival of the microbe sufficiently so that the host immune system can properly clear the infection. Such approaches can have some advantages over traditional antimicrobial therapy. For instance, there is a weaker selection for the emergence and spread of drug resistance, as the compounds only act in the context of the host. Similarly, by crippling a microbe’s anti-immunity functions, the host immune system may now be able to readily eliminate the pathogen and be better primed for future encounters.This latter feature may be particularly useful when considering new therapeutic approaches for chronic and recurrent microbial infections. It is in this context that the screening for compounds that inhibit virulence-associated secretion systems and immunoevasion-specific virulence factors becomes attractive. It is possible that limited rounds of pathogen replication can properly prime the immune system without major damage. In the context of our own work, we determined that blocking the synthesis of lipopolysaccharide in C. trachomatis with small-molecule LpxC inhibitors does not lead to cidal or static effects, as seen in other bacteria [19]. Instead, C. trachomatis that lacks lipopolysaccharide replicates robustly within intracellular vacuoles, but is unable to transition into the invasive form – the elementary body – essentially aborting its dissemination in vitro. Given that elementary bodies translocate a wide range of effectors, many with predicted functions related to innate immune evasion [14], could such a therapy now limit the pathologies associated with Chlamydia infection while allowing the development of lasting immunity? We also recently determined that inhibitors specific for CPAF, a major secreted protease with potential roles in blocking innate immune responses [12], led to a five- to ten-fold reduction of bacterial replication in vitro and the activation of pyroptotic cell death pathways in infected epithelial cells [20]. What would be the consequences of inactivating CPAF activity during an acute infection in an animal? In one scenario, inhibition of CPAF may lead to increased inflammatory damage – a less than optimal outcome. In another scenario, limited localized inflammation may lead to more effective clearance. Either way, it will be important to determine how cellular and humoral immune responses to acute Chlamydia infections differ upon inhibition of CPAF. How does the timing of administration of such an antivirulence factor influence bacterial replication, dissemination and pathology? These are important proof-of-principle questions that we can now begin to address for such anti-infective therapies. A thorough testing of these compounds in animal models is a must if we are to determine whether treatment with anti-infectives can deliver on the promise that they can not only provide protection against primary acute infections, but also limit pathology, recurrent infections, and be superior to conventional antimicrobial therapy.Whether anti-infectives such as CPAF inhibitors can make effective, commercially viable therapeutics is a different question. Issues such as cost, public health priorities and how any anti-infective compound compares to current antibiotic therapies will be the subjects of much debate. Furthermore, health market constraints may easily limit the development any new therapy at preclinical stages, even if the compounds prove to be highly effective. Nonetheless, the lessons that can be learned about disease progression and immunity based on targeted – either genetic or pharmacological – ablation of virulence factors can potentially pave the way for better therapies and a more comprehensive understanding of chlamydial and other chronic bacterial diseases.AcknowledgementThe author is indebted to R Rank for spirited discussions.Financial & competing interests disclosureWork in the author’s laboratory is supported by funds form the NIH/NIAID (grant numbers 5R01AI081694 and 5R21AI085238) and the Burroughs Wellcome Program in the Pathogenesis of Infectious Diseases. Provisional patent applications have been filed on some of the compounds described in this manuscript. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Gottlieb SL, Brunham RC, Byrne GI, Martin DH, Xu F, Berman SM. Introduction: the natural history and immunobiology of Chlamydia trachomatis genital infection and implications for Chlamydia control. J. Infect. Dis.201(Suppl. 2),S85–S87 (2010).Crossref, Medline, Google Scholar2 Gottlieb SL, Martin DH, Xu F, Byrne GI, Brunham RC. Summary: the natural history and immunobiology of Chlamydia trachomatis genital infection and implications for Chlamydia control. J. Infect. Dis.201(Suppl. 2),S190–S204 (2010).Crossref, Medline, CAS, Google Scholar3 Rekart ML, Brunham RC. Epidemiology of chlamydial infection: are we losing ground? Sex. Transm. 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Cell Host Microbe10,21–32 (2011).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByA 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of Chlamydia trachomatismBio, Vol. 6, No. 1Mutations in hemG Mediate Resistance to Salicylidene Acylhydrazides, Demonstrating a Novel Link between Protoporphyrinogen Oxidase (HemG) and Chlamydia trachomatis InfectivityJournal of Bacteriology, Vol. 195, No. 18 Vol. 7, No. 4 Follow us on social media for the latest updates Metrics History Published online 23 March 2012 Published in print April 2012 Information© Future Medicine LtdKeywordsanti-infective Chlamydia therapyvirulenceAcknowledgementThe author is indebted to R Rank for spirited discussions.Financial & competing interests disclosureWork in the author’s laboratory is supported by funds form the NIH/NIAID (grant numbers 5R01AI081694 and 5R21AI085238) and the Burroughs Wellcome Program in the Pathogenesis of Infectious Diseases. Provisional patent applications have been filed on some of the compounds described in this manuscript. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download