Clinical Microbiology Reviews

A Publication of the American Society for Microbiology

VOLUME 24 ● JULY 2011 ● NUMBER 3

CONTENTS/SUMMARIES

Review and International Recommendation of Methods for Typing Neisseria gonorrhoeae Isolates and Their Implications for Improved Knowledge of Gonococcal Epidemiology, Treatment, and Biology. Magnus Unemo and Jo-Anne R. Dillon ...... 447–458

Summary: Gonorrhea, which may become untreatable due to multiple resistance to available antibiotics, remains a public health problem worldwide. Precise methods for typing Neisseria gonorrhoeae, together with epidemiological information, are crucial for an enhanced understanding regarding issues involving epidemiology, test of cure and contact tracing, identifying core groups and risk behaviors, and recommending effective antimicrobial treatment, control, and preventive measures. This review evaluates methods for typing N. gonorrhoeae isolates and recommends various methods for different situations. Phenotypic typing methods, as well as some now-outdated DNA-based methods, have limited usefulness in differentiating between strains of N. gonorrhoeae. Genotypic methods based on DNA sequencing are preferred, and the selection of the appropriate genotypic method should be guided by its performance characteristics and whether short-term epidemiology (microepidemiology) or long-term and/or global epidemiology (macroepidemiology) matters are being investigated. Currently, for microepide- miological questions, the best methods for fast, objective, portable, highly discriminatory, reproducible, typeable, and high-throughput characterization are N. gonorrhoeae multiantigen sequence typing (NG-MAST) and full- or extended-length porB gene sequencing. However, pulsed-ﬁeld gel electrophoresis (PFGE) and Opa typing can be valuable in speciﬁc situations, i.e., extreme microepidemiology, despite their limitations. For macroepidemiological studies and phylogenetic studies, DNA sequencing of chromosomal housekeeping genes, such as multilocus sequence typing (MLST), provides a more nuanced understanding.

Onchocerciasis: the Role of Wolbachia Bacterial Endosymbionts in Parasite Biology, Disease Pathogenesis, and Treatment. Francesca Tamarozzi, Alice Halliday, Katrin Gentil, Achim Hoerauf, Eric Pearlman, and Mark J. Taylor ...... 459–468

Summary: The discovery of Wolbachia intracellular bacteria within ﬁlarial nematodes, including Onchocerca volvulus, the causative agent of onchocerciasis or “river blindness,” has delivered a paradigm shift in our understanding of the parasite’s biology, to where we now know

Continued on following page Continued from preceding page

that the bacterial endosymbionts are essential for normal development of larvae and embryos and may support the long-term survival of adult worms. The apparent mutualistic dependency has also offered a novel approach to the treatment of onchocerciasis through the use of antibiotics to eliminate Wolbachia, delivering for the first time a treatment which has significant macrofilaricidal efficacy. Studies with other filarial nematode species have also highlighted a role for Wolbachia in transmission and infection of the mammalian host through a fascinating manipulation of mast cell-mediated vasodilation to enhance infectivity of vector-borne larvae. Wolbachia has also been identified as the principal driver of innate and adaptive Th1 inflammatory immunity, which can either contribute to disease pathogenesis or, with the Wolbachia- mediated recruitment of mast cells, enhance infectivity. The Wolbachia activation of innate inflammation also drives inflammatory adverse events in response to chemotherapy with either diethylcarbamazine (DEC) or ivermectin. In this review we summarize the experimental and field trial data which have uncovered the importance of Wolbachia symbiosis in onchocerciasis.

Mechanisms of Obligatory Intracellular Infection with Anaplasma phagocytophilum. Yasuko Rikihisa...... 469–489

Summary: Anaplasma phagocytophilum persists in nature by cycling between mammals and ticks. Human infection by the bite of an infected tick leads to a potentially fatal emerging disease called human granulocytic anaplasmosis. A. phagocytophilum is an obligatory intracellular bacterium that replicates inside mammalian granulocytes and the salivary gland and midgut cells of ticks. A. phagocytophilum evolved the remarkable ability to hijack the regulatory system of host cells. A. phagocytophilum alters vesicular traffic to create an intracellular membrane- bound compartment that allows replication in seclusion from lysosomes. The bacterium down- regulates or actively inhibits a number of innate immune responses of mammalian host cells, and it upregulates cellular cholesterol uptake to acquire cholesterol for survival. It also upregulates several genes critical for the infection of ticks, and it prolongs tick survival at freezing temperatures. Several host factors that exacerbate infection have been identified, including interleukin-8 (IL-8) and cholesterol. Host factors that overcome infection include IL-12 and gamma interferon (IFN-␥). Two bacterial type IV secretion effectors and several bacterial proteins that associate with inclusion membranes have been identified. An understanding of the molecular mechanisms underlying A. phagocytophilum infection will foster the development of creative ideas to prevent or treat this emerging tick-borne disease.

Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or I␬B␣ Deﬁciency. Capucine Picard, Jean-Laurent Casanova, and Anne Puel ...... 490–497

Summary: Autosomal recessive IRAK-4 and MyD88 deficiencies predispose affected patients to recurrent invasive pyogenic bacterial infection. Both defects result in the selective impairment of cellular responses to Toll-like receptors (TLRs) other than TLR3 and of cellular responses to most interleukin-1 receptors (IL-1Rs), including IL-1R, IL-18R, and IL-33R. Hypomorphic mutations in the X-linked NEMO gene and hypermorphic mutations in the autosomal IKBA gene cause X-linked recessive and autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) syndromes. Both of these defects impair NF-␬B-mediated cellular responses to multiple receptors, including TLRs, IL-1Rs, and tumor necrosis factor receptors (TNF-Rs). They therefore confer a much broader predisposition to infections than that for IRAK-4 and MyD88 deficiencies. These disorders were initially thought to be rare but have now been diagnosed in over 170 patients worldwide. We review here the infectious diseases affecting patients with inborn errors of NF-␬B-dependent TLR and IL-1R immunity.

Mycoplasma genitalium: from Chrysalis to Multicolored Butterﬂy. David Taylor-Robinson and Jørgen Skov Jensen ...... 498–514

Summary: The history, replication, genetics, characteristics (both biological and physical), and factors involved in the pathogenesis of Mycoplasma genitalium are presented. The latter factors include adhesion, the inﬂuence of hormones, motility, possible toxin production, and immu- nological responses. The preferred site of colonization, together with current detection proce-

Continued on following page Continued from preceding page

dures, mainly by PCR technology, is discussed. The relationships between M. genitalium and various diseases are highlighted. These diseases include acute and chronic nongonococcal urethritis, balanoposthitis, chronic prostatitis, and acute epididymitis in men and urethritis, bacterial vaginosis, vaginitis, cervicitis, pelvic inflammatory disease, and reproductive disease in women. A causative relationship, or otherwise strong association, between several of these diseases and M. genitalium is apparent, and the extent of this, on a subjective basis, is presented; also provided is a comparison between M. genitalium and two other genital tract-orientated mollicutes, namely, Mycoplasma hominis, the first mycoplasma of human origin to be discov- ered, and Ureaplasma species. Also discussed is the relationship between M. genitalium and infertility and also arthritis in both men and women, as is infection in homosexual and immunodeficient patients. Decreased immunity, as in HIV infections, may enhance mycoplas- mal detection and increase disease severity. Finally, aspects of the antimicrobial susceptibility and resistance of M. genitalium, together with the treatment and possible prevention of myco- plasmal disease, are discussed.

Expert Systems in Clinical Microbiology. Trevor Winstanley and Patrice Courvalin...... 515–556

Summary: This review aims to discuss expert systems in general and how they may be used in medicine as a whole and clinical microbiology in particular (with the aid of interpretive reading). It considers rule-based systems, pattern-based systems, and data mining and intro- duces neural nets. A variety of noncommercial systems is described, and the central role played by the EUCAST is stressed. The need for expert rules in the environment of reset EUCAST breakpoints is also questioned. Commercial automated systems with on-board expert systems are considered, with emphasis being placed on the “big three”: Vitek 2, BD Phoenix, and MicroScan. By necessity and in places, the review becomes a general review of automated system performances for the detection of speciﬁc resistance mechanisms rather than focusing solely on expert systems. Published performance evaluations of each system are drawn together and commented on critically.

Pathogenesis and Pathophysiology of Pneumococcal Meningitis. Barry B. Mook-Kanamori, Madelijn Geldhoff, Tom van der Poll, and Diederik van de Beek ...... 557–591

Summary: Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae, which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagu- lation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal mod- els continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy.

Pathogenesis of Chagas’ Disease: Parasite Persistence and Autoimmunity. Antonio R. L. Teixeira, Mariana M. Hecht, Maria C. Guimaro, Alessandro O. Sousa, and Nadjar Nitz ...... 592–630

Summary: Acute Trypanosoma cruzi infections can be asymptomatic, but chronically infected individuals can die of Chagas’ disease. The transfer of the parasite mitochondrial kinetoplast DNA (kDNA) minicircle to the genome of chagasic patients can explain the pathogenesis of the disease; in cases of Chagas’ disease with evident cardiomyopathy, the kDNA minicircles Continued on following page Continued from preceding page

integrate mainly into retrotransposons at several chromosomes, but the minicircles are also detected in coding regions of genes that regulate cell growth, differentiation, and immune responses. An accurate evaluation of the role played by the genotype alterations in the autoimmune rejection of self-tissues in Chagas’ disease is achieved with the cross-kingdom chicken model system, which is refractory to T. cruzi infections. The inoculation of T. cruzi into embryonated eggs prior to incubation generates parasite-free chicks, which retain the kDNA minicircle sequence mainly in the macrochromosome coding genes. Crossbreeding transfers the kDNA mutations to the chicken progeny. The kDNA-mutated chickens develop severe cardiomyopathy in adult life and die of heart failure. The phenotyping of the lesions revealed that cytotoxic CD45, CD8ϩ ␥␦, and CD8␣ϩ T lymphocytes carry out the rejection of the chicken heart. These results suggest that the inﬂammatory cardiomyopathy of Chagas’ disease is a genetically driven autoimmune disease.

AUTHOR’S CORRECTION

The Airway Epithelium: Soldier in the Fight against Respiratory Viruses. Marjolaine Vareille, Elisabeth Kieninger, Michael R. Edwards, and Nicolas Regamey ...... 631