Typhi and  Paratyphi A, collectively known as typhoidal , are causal agents for a serious, invasive (bacteraemic), sometimes fatal disease of humans called typhoid fever or paratyphoid fever (also called enteric fevers).  Typhi, the lineage causing typhoid fever, is the main group; while Paratyphi A, the lineage causing paratyphoid fever, belongs to the second group which comprises a set of three paratyphoid types (the other two being  Paratyphi C and -tartrate-negative  Paratyphi B). All of these lineages are adapted to humans, with Typhi and  Paratyphi A being strictly restricted to growth in humans, and  Paratyphi C being able to establish infections in experimental animals quite easily (at moderate infection doses); the host-restriction status of -tartrate-negative  Paratyphi B is so far unclear. Representing an update on the version published in the first edition of this book that very thoroughly summarized the knowledge available at that time, most of the emphasis in this chapter is on typhoid fever due to  Typhi in relation to its taxonomy, genomics and genetics, diagnosis, association with disease, mechanisms of invasion and pathogenesis, and antibiotic and vaccine strategies to minimize its impact. The impact of typhoidal  on human hosts is indeed very large. In 2000, typhoid fever caused over 20 million illnesses and more than 200 000 deaths, whereas paratyphoid fever caused an estimated 5.4 million illnesses worldwide. The greatest burden of illness was suffered by infants, children and adolescents in south-central and south-eastern Asia. Typhoid and paratyphoid fever usually present as clinically similar acute febrile illnesses; accurate diagnosis relies on confirmation by laboratory tests. Paratyphoid fever is usually the result of infection by . Paratyphi A, and recent reports show an increasing incidence of . Paratyphi A causing enteric fever in developing counties in Asia and show that the earlier notion that paratyphoid fever is less serious than typhoid fever is not correct. The organism must be cultured and identified to make a clear diagnosis; clinical symptoms alone are not adequate. Culture from blood is less sensitive than bone marrow culture and often gives negative results even when bone marrow cultures are positive, but it is usually the practical first choice for patient diagnosis and for epidemiologic studies of the burden of typhoid and paratyphoid fever. Because of a lack of good diagnostic tools, and because the sites of endemic disease are often deficient in clinical and laboratory facilities, the extent of the burden of enteric fever is often poorly characterized in much of the world, especially in sub-Saharan Africa.

Non-typhoidal  includes more than 2400 serotypes of that causes primarily enteric disease in human patients.  has a highly sophisticated molecular machinery that includes two type III secretion systems, which translocate bacterial effector proteins directly into the host cell cytosol. These systems subvert host cell pathways benefitting the pathogen, which ultimately allows for invasion of epithelial cells of the intestine, and intracellular survival and replication. These two critical steps in  pathogenesis are crucial for inducing intestinal inflammation, host colonization, and dissemination to systemic sites of infection.  triggers several somewhat overlapping pro-inflammatory pathways, which although they may play a favourable role mitigating systemic spread of infection, also favour the organism since  has evolved mechanisms that make it highly adapted to the inflamed intestinal environment. Thus, the -elicited inflammatory response leads to competitive advantage of this organism over the intestinal microbiota.

, an enteropathogenic species belonging to the genus , is widely distributed in nature and affects both humans and animals. In the past 10 years, this microorganism has been extensively studied in numerous publications, focusing on molecular biology, basic genetics, virulence, epidemiology and genomics. This chapter provides a comprehensive overview of all the biological and medical aspects relating to this bacterial pathogen, relating well-accepted data to recent information. Due to the versatile nature of , a thorough knowledge of this species is not achievable and it is expected that future research will bring further enlightenment.

The Gram-positive bacterium  survives as a saprophyte in soil but is also a foodborne facultative intracellular pathogen that is capable of causing severe invasive disease in susceptible human populations. While disease in healthy individuals is usually a self-limiting gastroenteritis, susceptible individuals can develop bacteraemia, CNS infections, placental infections, and other forms of disease associated with high mortality rates. Over the years,  has become a model system of intracellular pathogenesis, and studies of this organism within tissue culture and animal models of infection have revealed diverse aspects of host signalling cascades, cell physiology and immune responses. An additional benefit of research has been the development of attenuated strains as vaccine vectors for the delivery of a variety of antigens. This chapter reviews interesting aspects of  physiology, pathogenesis and disease, and highlights the diversity of cellular processes that can be explored via the interactions of a single bacterium with its mammalian host.

Urinary tract infections (UTI) are amongst the most common to affect humans, mostly women, and the gender and age distributions are characteristic. This is surprising because the bladder is a cul-de-sac in contact with the environment only through the urethra. The explanation seems to be that some individuals have distinct susceptibility factors and that uropathogens have highly effective virulence mechanisms. Counteracting these the urinary tract also has a range of defence mechanisms. Diagnosis is complicated by the high risk that urine becomes contaminated during collection and the ease with which bacteria grow in urine. This has led to the definition of significant bacteriuria, which is, however, not always associated with true infection. The spectrum of UTI, particularly in women, includes covert bacteriuria, which is not associated with true infection and a range of infections from acute to chronic, including cystitis and pyelonephritis. The most common route of infection is ascending from the bladder to the kidney but it may be descending when infection of the kidney is blood-borne.

Urinary tract infections (UTIs), caused primarily by uropathogenic (UPEC), are among the most common bacterial infections in humans, costing billions of dollars annually in medical expenses and causing significant morbidity with recurrent and chronic disease. Many details of the molecular pathogenesis of UPEC UTI have been unveiled through recent advances in a murine model of cystitis. Following ascension to the bladder, UPEC bind and invade superficial facet cells of the uroepithelium via type 1 pili. Uropathogens are able to evade innate cellular defences, in part, by proceeding through an intracellular cascade in which UPEC replicate within the facet cell cytoplasm, forming densely packed intracellular bacterial communities (IBCs). Egress of filamentous bacteria from IBCs can initiate subsequent rounds of IBC formation, thereby perpetuating acute infection. UPEC also invade the transitional epithelium, establishing latent, non-replicating reservoirs that resist antibiotic therapy and may initiate same-strain recurrent infection. UPEC employ a variety of additional molecular strategies to facilitate infection and to delay and subvert the host immune response. Finally, novel therapeutic and preventive strategies such as antivirulence compounds and vaccines may be necessary to combat the growing threat of antimicrobial resistance.

Urinary tract infections (UTIs) are common nosocomial infections.  is a frequent cause of these infections in individuals with abnormal urinary tracts or using indwelling catheters (CAUTIs). Since most research on non- uropathogens has been conducted on , this organism serves a model of pathogenesis for these types of infections. To establish and infect the urinary tract,  must possess virulence factors to adapt to the local environment and to evade the host immune response. The virulence factors known to be involved in UTIs caused by include adhesins, motility, biofilm formation, immunoavoidance, toxins and nutrient acquisition. The annotation of the  genome and transcriptome profiling have allowed for better understanding of the disease process caused by this bacteria in the urinary tract. This chapter reiterates previous works discussed in the first edition and introduce current research being performed on this uropathogen.

Bacterial agents of sexually transmitted diseases (STDs) constitute a major public health burden in both industrialized and developed countries. They include , the causative agent of gonorrhoea; , which causes chlamydial infections and their sequelae; , the aetiologic agent of syphilis;  (formerly called ), which causes granuloma inguinale (donovanosis); , the aetiologic agent of chancroid; and some species of  and  that are occasional causes of consequential sexually transmitted infections (STIs). Bacterial STD syndromes range from serious and/or life-threatening conditions, such as syphilis, to debilitating syndromes with long-term consequences, including pelvic inflammatory disease, endometritis, ectopic pregnancy, and infertility; in addition, less serious pathological presentations such as self-limiting urethritis, cervicitis and fever are associated with bacterial STIs. Interestingly, three of the diseases that are subject in the USA to mandatory reporting to public health agencies are caused by bacterial STD agents: gonorrhoea, chlamydia and syphilis.

In general, the pathogeneses of bacterial STDs include both microbial factors and host inflammatory reactions to the infection. As common features, bacterial STDs are more prevalent among adolescents than older adults, suggesting that immune resistance may build up in adults over time; they are treatable with reliable antimicrobials if detected early; they may have irreversible sequelae; they can increase the risk of viral STIs, such as human papillomavirus (HPV) and human immunodeficiency virus (HIV); their transmission is usually via direct genital mucosal contact; and there are no human vaccines currently available.

This chapter presents current information on the burden of infection, aetiological agents, clinical presentation and features, microbiology, pathogenesis (including microbial and host contribution to disease onset and progression), diagnosis, treatment, and state-of-the-art approaches to prevention and control of chlamydia, gonorrhoea, syphilis, chancroid and mycoplasmal diseases. For the purpose of providing a clinically relevant overview of these common bacterial STDs, we have referenced and summarized information from the current CDC STD Treatment Guidelines and other recent reviews.

Uncultivable pathogenic treponemes represent bacterial species and subspecies that are obligate pathogens of humans and animals.  subsp. causes sexually transmitted syphilis, a multistage disease characterized in humans by localized, disseminated, and chronic forms of infection. Causative agents of endemic treponematoses comprise  subsp.  (agent of yaws),  subsp.  (agent of bejel) and  (agent of pinta) causing milder, non-venereal transmitted diseases affecting skin, bones and joints. Closely related treponemes, simian  Fribourg-Blanc and , cause infections in non-human primates and rabbits, respectively.  is not pathogenic to humans, whereas simian  Fribourg-Blanc has been shown to cause experimental human infections. All human treponematoses share remarkable similarities in pathogenesis and clinical manifestations, consistent with the high genetic and antigenic relatedness of their aetiological agents. Pathogenic treponemes are characterized by low toxicity, high invasiveness, and high immuno-evasiveness. Moreover, treponemes are pathogens able to infect almost any type of human tissues, i.e. showing broad tissue tropism. All these pathogenic treponemes cannot be continuously cultivated under in vitro conditions. All uncultivable pathogenic treponemes have a reduced genome (~1.14 Mb) and represent clonal bacteria with identical genome structure having only minimal genetic differences in their genomic sequences.

 is a small, Gram-negative coccobacillus that causes the genital ulcer disease known as chancroid. Chancroid increases the risk for transmission and acquisition of HIV-1. The prevalence of the disease is unknown due to syndromic management of genital ulcer disease, but outbreaks continue to be reported in developing countries and in populations with high numbers of sexual partners. Patients with chancroid seek medical care several weeks after acquiring the infection when they become symptomatic and complain of painful genital ulcers that are often associated with suppurative inguinal lymphadenopathy. Research has focused on identifying virulence factors, the most notable of which play roles in adherence to extracellular matrix components and resistance to both phagocytosis and complement-mediated killing. Single-dose antibiotic therapy with macrolides or third-generation cephalosporins or with fluoroquinolones remains effective for the treatment of chancroid, but patients remain susceptible to reinfection as protective immunity does not develop.

The obligate intracellular bacterium  is arguably the most common sexually transmitted bacterial pathogen worldwide and a major cause of blindness in underdeveloped countries. Urogenital chlamydial infection is mostly asymptomatic or exhibits very mild symptoms. However, if left untreated, it can result in devastating complications, with tubal factor infertility and pelvic inflammatory diseases being the most common outcomes, and ectopic pregnancy being the most dangerous consequence. Like other chlamydiae,  has a unique developmental cycle, which consists of two distinct cellular forms, and is accompanied by a temporal expression pattern of genes and small non-coding RNAs.  strains display strikingly different tissue tropisms, which correlate with a small number of genes differentially existing in their genomes. A conserved plasmid has been identified as a critical virulence factor. A long-awaited transformation system developed on the basis of the plasmid is anticipated to greatly facilitate the understanding of chlamydial biology in coming years.

 is a bacterial pathogen responsible for gonorrhoea and various sequelae that tend to occur when asymptomatic infection ascends within the genital tract or disseminates to distal tissues. Global rates of gonorrhoea continue to rise, facilitated by the emergence of broad-spectrum antibiotic resistance that has recently afforded the bacteria ‘superbug’ status.  is exquisitely adapted to life in humans, having evolved novel strategies to succeed in their restricted mucosal niche. Gonococci also represent a paradigm for bacterial immune evasion due to its genetically plastic lifestyle and ability to directly suppress otherwise protective adaptive responses, allowing the bacteria to persist within an infected individual and re-infect individuals who have had prior infection. This chapter highlights unique aspects of the gonococcal lifestyle, including consideration of genetic and biochemical processes that allow ongoing antigenic variability and molecular interactions at the host–pathogen interface that contribute to the ongoing success of this globally important pathogen.

Bacterial vaginosis (BV) is a dysbiostic condition of the vagina that can lead to vaginal symptoms or asymptomatic infections. In both cases, BV influences the health of women by increasing risk for acquiring several sexually transmitted pathogens, and, when a woman is pregnant, by influencing the risk for preterm labour. The inability to identify a lone bacterial species that fits Koch’s postulates for disease causation, and the high rate of recurrence despite appropriate treatment hint at the complex nature of this condition. New insights about BV and associated bacterial communities will likely flow from studies at the intersection of molecular microbiology, conventional microbiology, genomics, immunity, and the ecological determinants of the vaginal bacterial population.

Respiratory tract infections are among the most common and important problems in clinical medicine. The approach to these infections begins with a basic understanding of the pathophysiology of the respiratory tract and how immune defences interact with pathogens. A number of distinct clinical syndromes can be defined which help physicians and clinical microbiologists develop a differential diagnosis of potential infecting pathogens. The type and severity of infection is often modulated by the medical characteristics of the patient, circumstances surrounding infection, geography and environmental exposures. Multiple laboratory test methodologies are available to aid clinical diagnosis and close communication between clinicians and laboratory personnel can optimise the efficiency and cost-effectiveness of diagnosis. Molecular testing for respiratory viruses has become widely used in the clinical setting and will expand to include other pathogens of the respiratory tract.

 is the agent of whooping cough, a highly contagious respiratory disease, dramatic for infants and also for elderly and pregnant women. This bacterium secretes adhesins and toxins acting in synergy to cause local and systemic cytopathogenic effects observed during the disease. Intensive vaccination of infants and young children with killed bacteria allowed an important decrease in mortality and morbidity. However, vaccination has led to a change in the transmission of the disease due to the short duration of vaccinal, as well as infectious, immunity and the lack of vaccinal or natural boosters. In highly vaccinated regions, the disease affects now adolescents and adults who contaminate non-vaccinated infants. Thanks to the development of vaccines containing only a few purified and detoxified bacterial proteins, vaccine boosters have been introduced in many countries. Biological diagnoses are needed since the clinical symptoms can be atypical in adolescents and adults. These diagnoses are in priority culture, in order to follow the evolution of the  species and bacterial macrolides susceptibility, and real-time PCR, a sensitive and rapid diagnosis. It is recommended to treat the infected subject but also the contact cases in order to stop the transmission of this very contagious disease by macrolides.

Research on  has revealed key aspects in the study of infectious diseases and pathogen evolution, but pneumococci remain a major cause of morbidity and mortality. New insights into the pathogenic mechanisms of this species confirmed the key role of the capsular polysaccharide but have also identified the important functions played by proteins in the interaction with the host. The capacity of pneumococci to exchange DNA is central in the adaptation to human-imposed selective pressures and our understanding of the mechanisms underlying competence is raising new questions about the evolution of these bacteria. A greater knowledge of the biology of pneumococci resulted in new diagnostic tests that together with a revision of the breakpoints defining resistance to penicillin and the advent of conjugate vaccines, are changing our understanding of the burden of pneumococcal disease and our approaches to prevent and treat infections by this important pathogen.

 is a Gram-negative bacterium that is frequently found in the flora of the mouth, skin and intestines as well as in natural environments.  is an opportunistic pathogen that can cause severe hospital-acquired infections such as septicaemia, pneumonia, urinary tract infection and soft tissue infection in debilitated individuals. This species is well-known for its ability to accumulate and transfer drug-resistance determinants such as extended-spectrum β-lactamase (ESBL). Treatment of serious infection with ESBL-producing  is extremely difficult because the organisms are increasingly resistant to multiple antibiotics, which may be caused by very complex mechanisms. The pathogenicity of  is multifactorial including LPS, capsule, urease, adhesins, outer-membrane proteins and biofilms. Vaccines have been tested but no effective products are in use.

 is part of the normal bacterial flora in the nasopharynx of children, although over the past two decades, it has emerged as a significant bacterial pathogen and not simply a commensal colonizer.  is a common bacterial species cultured from the nasopharynx of children during otitis media episodes, with the patterns of nasopharyngeal colonization by microorganisms being important determinants for otitis media disease. Treatment of otitis media is not always appropriate, and the long-term overuse of antibiotics in otitis media reduces the effectiveness of treatment and places children at an increased risk of antibiotic-resistant infections. Because there is currently no ideal treatment for otitis media, an alternative to the use of antibiotics is vaccination. To date, several  vaccine candidates have been described, which may be effective in reducing the burden of otitis media disease.

Mycoplasmas and ureaplasmas are important human pathogens of adults and infants, predominantly affecting the respiratory and urogenital tracts. Being the smallest free-living organisms, they have evolved characteristics that make them unique among the prokaryotes and the focus of investigations aimed at learning what constitutes the minimal set of genes that can support independent life. Development of molecular-based methods for detection and characterization of these fascinating organisms over the past two decades has enabled more rapid and accurate diagnosis as well as increased knowledge about their basic biology and the infections they cause. Much information has been learned from genome sequencing and proteomics. Genome sequencing that took months to years a decade ago can now be done in a matter of hours for only a few percent of the investment once required. This chapter reviews the classification, structure, pathogenesis, detection, identification, and typing methods for  and . Emergence and mechanisms involved in acquired antimicrobial resistance in these organisms is also discussed.

A great deal of information on the  genus, legionellosis, the microbial ecology, as well as its pathogenicity, diagnosis and treatment has been accumulated since this pathogen caused the first known outbreak in 1976. However, the control of legionellosis relies primarily on the diagnostic testing of patients and vigilant surveillance of water systems in healthcare facilities. PCR methods offer a useful alternative for the future as they can be utilized on primary specimens, are highly sensitive and specific, and can detect all serogroups of  as well as other species of that cause disease. If approaches utilizing testing algorithms combining culture and PCR methods are utilized they will also offer advantages during outbreak investigations. Additionally, reducing exposures to  and preventing disease will be improved when more is understood about the control of  in water systems and vaccination strategies for  are evaluated.

There are currently over 100 described species in the genus  (). Although  is overwhelmingly the most significant respiratory pathogen within the genus, several of the non-diphtheriae  spp. have been noted as emerging respiratory pathogens in the recent literature. Because  spp., as well as other ‘coryneform’ organisms, are routinely recovered from clinical specimens as part of the normal flora of the skin and upper respiratory tract and sequence-based identification has replaced more rapid and less expensive phenotypic methods as the gold standard method for definitive identification of the non-diphtheriae  spp., distinguishing commensal from disease-associated organisms remains a challenge for clinicians and clinical laboratories. In this chapter we review the classic pathogen, , and several non-diphtheriae  spp. that have been associated with respiratory infections or are recovered from respiratory specimens.

Tuberculosis (TB) is an ancient disease that continues to have a tremendous impact on global human health. Although the basic microbiology and pathophysiology of TB have been understood slowly over the last 100 years, complete genomic sequencing and improved molecular methods have yielded rapid new insights toward control. For example, DNA fingerprinting, such as by restriction fragment length polymorphism and spoliotyping, identify relationships between strains during TB outbreaks which can inform control strategies. Molecular microbiology offers advantages over traditional diagnostic methods, such as the Ziehl-Neelson stain, and solid or liquid media culture and drug susceptibility testing. Nucleic acid amplification tests such as automated PCR on a single-use contained-cartridge platform are rapidly changing the way TB diagnosis is approached in endemic and resource-limited settings. TB control urgently needs improved antimicrobial therapies and vaccines.

 is the aetiologic agent of leprosy affecting the skin and peripheral nerves. The infection is currently found in over 100 countries often located in high-burden areas against a low-burden background of cases. Clinical manifestations are varied and reflect the host’s immune response to the bacteria.  is susceptible to many modern antimicrobial agents but successful treatment requires prolonged therapy. While drug resistance to the primary drugs used for treatment appears minimal, single drug resistance has been reported to dapsone, rifampin and ofloxacin. The genome of  predicts severe metabolic restrictions due to a multitude of gene disruptions and deletions. Because of the inability to culture the  in vitro, animal models continue to provide a basis for testing new drugs and vaccines and offer insight into basic mechanisms of pathogenesis.

The non-tuberculous mycobacteria (NTM) include  and over 150 additional species of opportunistic pathogens whose source for human infection is the environment. NTM are normal inhabitants of soils, natural waters, drinking water distribution systems and household plumbing. NTM cause pulmonary, dermal, lymph node and disseminated infections in susceptible individuals. Risk factors for NTM disease include immunodeficiency, structural abnormalities of the chest, and exposure to dusts and inheritance of mutations leading to cystic fibrosis or α-1-antitrypsin-deficiency. The lipid-rich outer membrane of NTM is responsible, in part, for their resistance to disinfectants and commonly used antibiotics. Long term, multidrug regimens, often including rifampicin and clarithromycin, can result in disappearance of symptoms. Guidelines for the diagnosis and treatment of NTM infection are available.

Recognized species of rapidly growing mycobacteria have increased significantly in number over the past decade. Traditional biochemical methods of identification and differentiation have been replaced by molecular methods including sequence- and PCR-based methods. Recently, mass spectrometric methods have also been successfully utilized for discrimination to the species level. This chapter describes the current state-of-the-art for the identification of rapidly growing mycobacteria using molecular methods.

The central nervous system may be infected by a wide variety of bacteria, often as part of what is at first a bacteraemia but may later become a septicaemia, and sometimes as a result of extension from adjacent tissues. This chapter considers the pathophysiology of CNS bacterial infections and some of the host responses to these infections. In some cases an inadequate immune response may allow chronic infection to develop. Under other circumstances, notably meningitis, it is the host response that gives rise to tissue injury.

The pathogenesis of disease caused by  type b and non-typeable  involves multiple steps. Although similar mechanisms are used to promote colonization of the nasopharynx, both organisms express unique virulence determinants that dictate the spectrum of disease they are able to cause. A major difference is the expression of a PRP capsule by type b strains. This alone is sufficient to facilitate intravascular survival and the onset of invasive disease. Although it is a major determinant of virulence, the capsule has played a useful role as the basis of the highly successful  vaccine. In contrast, no such highly conserved virulence determinant is common to non-typeable strains of , which complicates the search for a candidate vaccine for this group of organisms. As a consequence, while disease due to type b stains is now rare, non-typeable strains continue to be a significant cause of morbidity and even mortality in children. New insights into non-typeable  virulence factors may give opportunities for vaccine or other strategies to prevent disease.

In many ways,  represents the prototypical pathogen for which molecular techniques have transformed in parallel the scope of basic, translational and clinical laboratory work. Fundamental biology, pathogenesis, epidemiology, diagnostics, treatment and vaccinology – meningococcal research in each of these areas has intensified in recent years with the availability of novel molecular technologies. Overall, this multidisciplined approach has revolutionized the management of meningococcal infection, making the prospect of worldwide disease control a very real possibility. At the same time, the wealth of emergent information on  makes it a challenging topic for clinicians and medical microbiologists to appreciate in its entirety. The goal of the current review, therefore, is to synthesize the broad molecular knowledge on this organism and present it in a manner that ties together the various sub-disciplines. It is our hope that this work can offer a detailed overview for clinical laboratorians and infectious disease physicians (the primary intended audience), integrating broad perspectives on this important pathogen.

 (group B streptococcus; GBS) is the major cause of invasive bacterial disease, including meningitis, in the neonatal period. GBS may breach the blood–brain barrier (BBB) and invade the central nervous system through transcellular mechanisms. Understanding the mechanisms of bacterial penetration across the BBB may help develop novel approaches to preventing bacterial meningitis. Commonly, between 36–50% of survivors of GBS meningitis more than 10 years after recovery from bacterial meningitis, will suffer permanent neurological sequelae, hearing loss, seizures and mental retardation. Here we review recent information on the bacterial virulence factors and mechanisms that direct host–pathogen interactions involved in the pathogenesis of GBS infection. New research on host signalling and inflammatory responses to GBS infection is summarized. An understanding of the complex interplay between GBS and the host provides valuable insight into pathogen evolution and highlights molecular targets for therapeutic intervention and development of a vaccine.

During this overview, we explore some of the conundrums of zoonoses. These range from defining what we actually mean by the term zoonoses, through to understanding the driving forces that facilitate emergence of new or promote the re-emergence of known zoonoses. In an attempt to embrace the complexity of these factors, we are now encouraged to take a holistic one-health approach whereby environmental, wildlife, veterinary, medical and social factors are considered collectively. Understandably, such intricate intertwined factors make it difficult to accurately model and predict the emergence and spread of infections. Despite the research investment into pathogen discovery, and prediction of expanding geographical ranges of known bacterial zoonoses, sadly little is done to control or reduce some of the major bacterial zoonoses such as brucellosis and leptospirosis. These have their largest impact upon those in resource-poor settings where these infections are endemic and their effects are profound.

 is a zoonotic, intracellular pathogen that causes a severe infectious disease called brucellosis in both animals and humans. The disease is transmitted from animal reservoirs to humans via (i) direct contact with infected materials; (ii) inhalation of infectious aerosols; and (iii) ingestion of contaminated food or water. Clinical symptoms of human brucellosis range from fever, chills, sweats, weakness, myalgia, arthralgia, depression, anorexia, spondylitis, endocarditis, to meningoencephalitis. Laboratory diagnosis of brucellosis has traditionally relied upon in vitro culture isolation of bacteria followed by various biochemical and serological tests. Recent development of molecular techniques such as PCR has facilitated rapid, sensitive and specific detection of  organisms. Despite continuous efforts in the past decades, there is still a great deal of unknowns about molecular mechanisms of  infection. Future research in this and related areas will help uncover new details on  pathogenesis at molecular level, and lead to novel control and prevention strategies against brucellosis.

The genus  is a diverse group of spore-forming bacteria.  species have implications in both medical and biodefence aspects of microbiology. This chapter attempts to summarize key molecular aspects of these bacteria (with an emphasis on ). Topics discussed include bacteriology (sporulation and germination), pathogenesis and disease progression, species differentiation and detection, virulence factors (toxin and capsule), vaccines (current and next-generation anthrax vaccines), and animal models of anthrax. As evidenced by the breadth of information covered within this chapter, there has been a great deal of research performed on  species for more than a century.

, the causative agent of bubonic plague, has three remarkable attributes. First, it causes the most severe of all human bacterial infections as judged by historical records. Second, the emergence of  occurred no later than 10 000 years ago and its dramatic evolution from an enteropathogen to agent of acute disease may still be in progress. Third, survival and multiplication of  within the host and flea vector are largely mediated by laterally transferred DNA and removal of this imported information converts the formidable plague bacillus into an innocuous entity capable of only transient survival in its mammalian host, flea vector, or natural environments. The purpose of this chapter is to integrate these features and to outline the physiological and molecular mechanisms that enable  to promote uncompromisingly destructive pathology.

The genus  comprises two major groups of spirochetes with at least 35 validated species. The first group contains  species within the  sensu lato complex, which is transmitted by the hard ticks  and is associated with Lyme disease or Lyme borreliosis. The second group of spirochetes includes  species transmitted mainly by soft ticks  with a few exceptions and is associated with human relapsing fever. The genus  possesses several genetic and phenotypic characteristics that are unique among prokaryotes.  species exist in nature in enzootic cycles primarily involving ticks and a wide range of animal and bird hosts. Both  and relapsing fever borreliae have a linear chromosome of approximately 910 kb and multiple linear and circular plasmids in a single cell. In this chapter, the key phenotypic and genetic features (including genome and other molecular characteristics) of  species, their association with clinical diseases, and diagnosis are discussed.

The  genus has grown from a single member in the early 1990s (i.e., ), to 31 validated species at this writing. Eleven species are considered to be aetiologic agents of emerging or re-emerging infectious diseases of humans. The widespread occurrence of  in mammalian reservoirs ranging from bats to whales, together with a broad spectrum of potentially life-threatening disease manifestations in infected hosts, has stimulated considerable research to elucidate the molecular pathogenesis, epidemiology and genetics of these bacteria.  share several general attributes. They are small (approximately 0.3 µm in width by 1 µm in length), Gram-negative, pleomorphic coccobacilli with a genomic GC content of ~40%. Bartonellae are facultative intracellular pathogens that employ haemotrophy (infection of erythrocytes) as a parasitic strategy. As such, their growth in vitro can only be accomplished in media containing blood or haem supplements, and even then they are notoriously fastidious and slow-growing. Arguably one of the most remarkable observations is that virtually every type of mammal surveyed has been found to serve as a host and/or reservoir for a subset of  species. Moreover, transmission of these bacteria is usually vectored through haematophagous arthropod ectoparasites of the host.

 is an intracellular bacterial pathogen that causes Q fever, with symptoms ranging from self-limited febrile illness, pneumonia, hepatitis, meningitis, encephalitis, pericarditis, myocarditis, endocarditis, to osteomyelitis. This chapter provides an update on  classification, epidemiology, identification, genetics, immunity, treatment and prevention.

Leptospirosis is a neglected infectious disease caused by spirochetes from the genus . It constitutes a major public health problem in developing countries, with outcomes ranging from subclinical infections to fatal pulmonary haemorrhage and Weil’s syndrome. The clinical diagnosis of leptospirosis is challenging due to the protean manifestations of the disease. To successfully establish an infection, leptospires bind to extracellular matrix compounds and host cells. The interaction of leptospires with pathogen recognition receptors is a fundamental issue in leptospiral immunity. The knowledge of evasion strategies employed by pathogenic leptospires to subvert the immune system is of extreme importance as they may represent targets for the development of new treatments and prophylactic approaches in leptospirosis. Besides, the recent availability of complete genome sequences for  spp. has led to important insights into their pathogenesis. This chapter presents an overview of the above aspects, highlighting the molecular microbiology of the pathogen.

, the causative agent of tularaemia, is a zoonotic intracellular pathogen that can be found in a very large number of species ranging from large mammals and vertebrates to invertebrates, arthropods and amoebas. Disease in humans often occurs in parallel with tularaemia in wild animals. Human infection can occur through aerosolization, direct contact with infected animals via arthropod vectors like ticks, mosquitos and biting flies.  subspecies  (type A) is one of the most infectious bacteria known and inhalation of as few as ten organisms can be sufficient to establish an infection in humans that if left untreated could be fatal. The success of  as a pathogen lies in its unique ability to adapt a lifestyle as an intracellular pathogen and to very timely subvert host defences both at extracellular and intracellular levels. Key events in the infection process are the ability to rapidly escape the phagosome after uptake by phagocytic cells and the ability to replicate to high levels inside the host cells without evoking a host inflammatory response

Human ehrlichioses are emerging, often life-threating, tick-borne diseases caused by obligately intracellular Gram-negative bacteria belonging to the genus . Ehrlichiae lack cell wall components, lipopolysaccharide and peptidoglycan. Ehrlichiae are maintained in the enzootic cycle involving persistently infected vertebrate hosts such as deer and the vector tick. Human monocytotropic ehrlichiosis (HME), caused by , is highly prevalent in the south-central, southeastern and mid-Atlantic regions of the United States. Molecular and serological evidence suggest a worldwide distribution of ehrlichiae.  resides in monocytes and causes moderate-to-severe flu-like illness characterised by non-specific symptoms such as fever, headache, myalgia, etc. The disease can progress to a severe toxic-shock-like syndrome with multiorgan failure, liver injury, meningoencephalitis, acute respiratory distress syndrome and myocarditis. Aberrant host inflammatory responses are implicated in the disease pathogenesis. Frequent laboratory findings in HME patients include leukopenia, thrombocytopenia and elevated hepatic transaminases. Clinical diagnosis frequently requires application of appropriate molecular diagnostics.  and newly discovered -like agent (EMLA) also cause human disease. Currently no vaccine is available against ehrlichiosis. Doxycycline is the drug of choice, and initiation of antibiotic therapy early during the infection is critical for its effectiveness.

 is a rickettsial pathogen transmitted by ixodid ticks.  colonises myeloid and non-myeloid cells and causes human granulocytic anaplasmosis – an important disease in the United States, Europe and Asia. Research has illustrated how  successfully invades and proliferates inside host cells, causing a systemic disease. Here, we address biology and the underlying mechanisms involved in bacterial pathogenesis and disease development. Clinical features, diagnostics and treatment are also discussed, as well as the contribution of the tick vector for microbial transmission.

Members of the genus  are small, obligate intracellular, Gram-negative bacteria that are distributed throughout the world. The lifecycle of  species involves arthropod vectors (ticks, fleas, mites and lice) and vertebrate hosts including humans. Transmitted through arthropod bites, human rickettsiosis may show clinical symptoms that range from fever, rash, myalgia, headache, meningitis, endocarditis, to lymphadenopathy/lymphangitis. Being an antibiotic-treatable disease, the ability to rapidly and accurately differentiate human rickettsiosis from other infections is critical. Although staining procedures and in vitro cultures have proven useful for detection of  species, they are increasingly superseded by nucleic acid amplification techniques that make rapid, sensitive and specific diagnosis and epidemiological tracking of human rickettsiosis outbreaks possible.

 spp. are obligate intracellular Gram-negative bacteria, with mites acting as both reservoirs and transmission vectors. The disease, caused by  spp. (commonly called scrub typhus) is characterised by early non-specific ‘flu-like’ symptoms, and sometimes a diffuse, macular and/or maculopapular rash and/or an eschar at the mite bite site. Complicated scrub typhus includes meningoencephalitis, respiratory and renal failure, which can develop into severe multiorgan failure. Scrub typhus is the leading cause of undifferentiated febrile illness in many regions of Asia. Despite its treatable nature, scrub typhus remains an underappreciated, neglected disease, mainly due to diagnostic difficulties and lack of awareness among medical staff. The development of diagnostics and vaccines difficulties challenging, due to the immunogenic diversity of  strains, the weak and transient cross-protection among divergent isolates, and the loss of heterologous protection within a few years after natural infection.