Showing papers in "Clinical Microbiology Reviews in 2021"

Tools and Techniques for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)/COVID-19 Detection.

Abstract: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory disease coronavirus 2 (SARS-CoV-2), has led to millions of confirmed cases and deaths worldwide. Efficient diagnostic tools are in high demand, as rapid and large-scale testing plays a pivotal role in patient management and decelerating disease spread. This paper reviews current technologies used to detect SARS-CoV-2 in clinical laboratories as well as advances made for molecular, antigen-based, and immunological point-of-care testing, including recent developments in sensor and biosensor devices. The importance of the timing and type of specimen collection is discussed, along with factors such as disease prevalence, setting, and methods. Details of the mechanisms of action of the various methodologies are presented, along with their application span and known performance characteristics. Diagnostic imaging techniques and biomarkers are also covered, with an emphasis on their use for assessing COVID-19 or monitoring disease severity or complications. While the SARS-CoV-2 literature is rapidly evolving, this review highlights topics of interest that have occurred during the pandemic and the lessons learned throughout. Exploring a broad armamentarium of techniques for detecting SARS-CoV-2 will ensure continued diagnostic support for clinicians, public health, and infection prevention and control for this pandemic and provide advice for future pandemic preparedness.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): a Systemic Infection.

Abstract: To date, seven identified coronaviruses (CoVs) have been found to infect humans; of these, three highly pathogenic variants have emerged in the 21st century. The newest member of this group, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected at the end of 2019 in Hubei province, China. Since then, this novel coronavirus has spread worldwide, causing a pandemic; the respiratory disease caused by the virus is called coronavirus disease 2019 (COVID-19). The clinical presentation ranges from asymptomatic to mild respiratory tract infections and influenza-like illness to severe disease with accompanying lung injury, multiorgan failure, and death. Although the lungs are believed to be the site at which SARS-CoV-2 replicates, infected patients often report other symptoms, suggesting the involvement of the gastrointestinal tract, heart, cardiovascular system, kidneys, and other organs; therefore, the following question arises: is COVID-19 a respiratory or systemic disease? This review aims to summarize existing data on the replication of SARS-CoV-2 in different tissues in both patients and ex vivo models.

Critical Determinants of Cytokine Storm and Type I Interferon Response in COVID-19 Pathogenesis.

Abstract: SUMMARY Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a rapidly evolving pandemic worldwide with at least 68 million COVID-19-positive cases and a mortality rate of about 2.2%, as of 10 December 2020. About 20% of COVID-19 patients exhibit moderate to severe symptoms. Severe COVID-19 manifests as acute respiratory distress syndrome (ARDS) with elevated plasma proinflammatory cytokines, including interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), C-X-C motif chemokine ligand 10 (CXCL10/IP10), macrophage inflammatory protein 1 alpha (MIP-1α), and chemokine (C-C motif) ligand 2 (CCL2), with low levels of interferon type I (IFN-I) in the early stage and elevated levels of IFN-I during the advanced stage of COVID-19. Most of the severe and critically ill COVID-19 patients have had preexisting comorbidities, including hypertension, diabetes, cardiovascular diseases, and respiratory diseases. These conditions are known to perturb the levels of cytokines, chemokines, and angiotensin-converting enzyme 2 (ACE2), an essential receptor involved in SARS-CoV-2 entry into the host cells. ACE2 downregulation during SARS-CoV-2 infection activates the angiotensin II/angiotensin receptor (AT1R)-mediated hypercytokinemia and hyperinflammatory syndrome. However, several SARS-CoV-2 proteins, including open reading frame 3b (ORF3b), ORF6, ORF7, ORF8, and the nucleocapsid (N) protein, can inhibit IFN type I and II (IFN-I and -II) production. Thus, hyperinflammation, in combination with the lack of IFN responses against SARS-CoV-2 early on during infection, makes the patients succumb rapidly to COVID-19. Therefore, therapeutic approaches involving anti-cytokine/anti-cytokine-signaling and IFN therapy would favor the disease prognosis in COVID-19. This review describes critical host and viral factors underpinning the inflammatory “cytokine storm” induction and IFN antagonism during COVID-19 pathogenesis. Therapeutic approaches to reduce hyperinflammation and their limitations are also discussed.

Mobile Oxazolidinone Resistance Genes in Gram-Positive and Gram-Negative Bacteria.

Abstract: Seven mobile oxazolidinone resistance genes, including cfr, cfr(B), cfr(C), cfr(D), cfr(E), optrA, and poxtA, have been identified to date. The cfr genes code for 23S rRNA methylases, which confer a multiresistance phenotype that includes resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A compounds. The optrA and poxtA genes code for ABC-F proteins that protect the bacterial ribosomes from the inhibitory effects of oxazolidinones. The optrA gene confers resistance to oxazolidinones and phenicols, while the poxtA gene confers elevated MICs or resistance to oxazolidinones, phenicols, and tetracycline. These oxazolidinone resistance genes are most frequently found on plasmids, but they are also located on transposons, integrative and conjugative elements (ICEs), genomic islands, and prophages. In these mobile genetic elements (MGEs), insertion sequences (IS) most often flanked the cfr, optrA, and poxtA genes and were able to generate translocatable units (TUs) that comprise the oxazolidinone resistance genes and occasionally also other genes. MGEs and TUs play an important role in the dissemination of oxazolidinone resistance genes across strain, species, and genus boundaries. Most frequently, these MGEs also harbor genes that mediate resistance not only to antimicrobial agents of other classes, but also to metals and biocides. Direct selection pressure by the use of antimicrobial agents to which the oxazolidinone resistance genes confer resistance, but also indirect selection pressure by the use of antimicrobial agents, metals, or biocides (the respective resistance genes against which are colocated on cfr-, optrA-, or poxtA-carrying MGEs) may play a role in the coselection and persistence of oxazolidinone resistance genes.

Advances in the Microbiology of Stenotrophomonas maltophilia.

Abstract: Stenotrophomonas maltophilia is an opportunistic pathogen of significant concern to susceptible patient populations. This pathogen can cause nosocomial and community-acquired respiratory and bloodstream infections and various other infections in humans. Sources include water, plant rhizospheres, animals, and foods. Studies of the genetic heterogeneity of S. maltophilia strains have identified several new genogroups and suggested adaptation of this pathogen to its habitats. The mechanisms used by S. maltophilia during pathogenesis continue to be uncovered and explored. S. maltophilia virulence factors include use of motility, biofilm formation, iron acquisition mechanisms, outer membrane components, protein secretion systems, extracellular enzymes, and antimicrobial resistance mechanisms. S. maltophilia is intrinsically drug resistant to an array of different antibiotics and uses a broad arsenal to protect itself against antimicrobials. Surveillance studies have recorded increases in drug resistance for S. maltophilia, prompting new strategies to be developed against this opportunist. The interactions of this environmental bacterium with other microorganisms are being elucidated. S. maltophilia and its products have applications in biotechnology, including agriculture, biocontrol, and bioremediation.

Viral Respiratory Pathogens and Lung Injury.

Abstract: Several viruses target the human respiratory tract, causing different clinical manifestations spanning from mild upper airway involvement to life-threatening acute respiratory distress syndrome (ARDS). As dramatically evident in the ongoing SARS-CoV-2 pandemic, the clinical picture is not always easily predictable due to the combined effect of direct viral and indirect patient-specific immune-mediated damage. In this review, we discuss the main RNA (orthomyxoviruses, paramyxoviruses, and coronaviruses) and DNA (adenoviruses, herpesviruses, and bocaviruses) viruses with respiratory tropism and their mechanisms of direct and indirect cell damage. We analyze the thin line existing between a protective immune response, capable of limiting viral replication, and an unbalanced, dysregulated immune activation often leading to the most severe complication. Our comprehension of the molecular mechanisms involved is increasing and this should pave the way for the development and clinical use of new tailored immune-based antiviral strategies.

Pathogenesis of Gram-Negative Bacteremia.

Abstract: Gram-negative bacteremia is a devastating public health threat, with high mortality in vulnerable populations and significant costs to the global economy. Concerningly, rates of both Gram-negative bacteremia and antimicrobial resistance in the causative species are increasing. Gram-negative bacteremia develops in three phases. First, bacteria invade or colonize initial sites of infection. Second, bacteria overcome host barriers, such as immune responses, and disseminate from initial body sites to the bloodstream. Third, bacteria adapt to survive in the blood and blood-filtering organs. To develop new therapies, it is critical to define species-specific and multispecies fitness factors required for bacteremia in model systems that are relevant to human infection. A small subset of species is responsible for the majority of Gram-negative bacteremia cases, including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii The few bacteremia fitness factors identified in these prominent Gram-negative species demonstrate shared and unique pathogenic mechanisms at each phase of bacteremia progression. Capsule production, adhesins, and metabolic flexibility are common mediators, whereas only some species utilize toxins. This review provides an overview of Gram-negative bacteremia, compares animal models for bacteremia, and discusses prevalent Gram-negative bacteremia species.

Molecular Epidemiology of Human Cryptosporidiosis in Low- and Middle-Income Countries.

Abstract: SUMMARY Cryptosporidiosis is one of the most important causes of moderate to severe diarrhea and diarrhea-related mortality in children under 2 years of age in low- and middle-income countries. In recent decades, genotyping and subtyping tools have been used in epidemiological studies of human cryptosporidiosis. Results of these studies suggest that higher genetic diversity of Cryptosporidium spp. is present in humans in these countries at both species and subtype levels and that anthroponotic transmission plays a major role in human cryptosporidiosis. Cryptosporidium hominis is the most common Cryptosporidium species in humans in almost all the low- and middle-income countries examined, with five subtype families (namely, Ia, Ib, Id, Ie, and If) being commonly found in most regions. In addition, most Cryptosporidium parvum infections in these areas are caused by the anthroponotic IIc subtype family rather than the zoonotic IIa subtype family. There is geographic segregation in Cryptosporidium hominis subtypes, as revealed by multilocus subtyping. Concurrent and sequential infections with different Cryptosporidium species and subtypes are common, as immunity against reinfection and cross protection against different Cryptosporidium species are partial. Differences in clinical presentations have been observed among Cryptosporidium species and C. hominis subtypes. These observations suggest that WASH (water, sanitation, and hygiene)-based interventions should be implemented to prevent and control human cryptosporidiosis in low- and middle-income countries.

Staphylococcus lugdunensis: a Skin Commensal with Invasive Pathogenic Potential.

Abstract: Staphylococcus lugdunensis is a species of coagulase-negative staphylococcus (CoNS) that causes serious infections in humans akin to those of S. aureus It was often misidentified as S. aureus, but this has been rectified by recent routine use of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) in diagnostic laboratories. It encodes a diverse array of virulence factors for adhesion, cytotoxicity, and innate immune evasion, but these are less diverse than those encoded by S. aureus It expresses an iron-regulated surface determinant (Isd) system combined with a novel energy-coupling factor (ECF) mechanism for extracting heme from hemoproteins. Small cytolytic S. lugdunensis synergistic hemolysins (SLUSH), peptides related to phenol-soluble modulins of S. aureus, act synergistically with β-toxin to lyse erythrocytes. S. lugdunensis expresses a novel peptide antibiotic, lugdunin, that can influence the nasal and skin microbiota. Endovascular infections are initiated by bacterial adherence to fibrinogen promoted by a homologue of Staphylococcus aureus clumping factor A and to von Willebrand factor on damaged endothelium by an uncharacterized mechanism. S. lugdunensis survives within mature phagolysosomes of macrophages without growing and is released only following apoptosis. This differs fundamentally from S. aureus, which actively grows and expresses bicomponent leukotoxins that cause membrane damage and could contribute to survival in the infected host. S. lugdunensis is being investigated as a probiotic to eradicate S. aureus from the nares of carriers. However, this is contraindicated by its innate virulence. Studies to obtain a deeper understanding of S. lugdunensis colonization, virulence, and microbiome interactions are therefore warranted.

The Changing Face of the Family Enterobacteriaceae (Order: "Enterobacterales"): New Members, Taxonomic Issues, Geographic Expansion, and New Diseases and Disease Syndromes.

Abstract: The family Enterobacteriaceae has undergone significant morphogenetic changes in its more than 85-year history, particularly during the past 2 decades (2000 to 2020). The development and introduction of new and novel molecular methods coupled with innovative laboratory techniques have led to many advances. We now know that the global range of enterobacteria is much more expansive than previously recognized, as they play important roles in the environment in vegetative processes and through widespread environmental distribution through insect vectors. In humans, many new species have been described, some associated with specific disease processes. Some established species are now observed in new infectious disease settings and syndromes. The results of molecular taxonomic and phylogenetics studies suggest that the current family Enterobacteriaceae should possibly be divided into seven or more separate families. The logarithmic explosion in the number of enterobacterial species described brings into question the relevancy, need, and mechanisms to potentially identify these taxa. This review covers the progression, transformation, and morphogenesis of the family from the seminal Centers for Disease Control and Prevention publication (J. J. Farmer III, B. R. Davis, F. W. Hickman-Brenner, A. McWhorter, et al., J Clin Microbiol 21:46-76, 1985, https://doi.org/10.1128/JCM.21.1.46-76.1985) to the present.

Microsporidiosis in Humans

Abstract: Microsporidia are obligate intracellular pathogens identified ∼150 years ago as the cause of pebrine, an economically important infection in silkworms. There are about 220 genera and 1,700 species of microsporidia, which are classified based on their ultrastructural features, developmental cycle, host-parasite relationship, and molecular analysis. Phylogenetic analysis suggests that microsporidia are related to the fungi, being grouped with the Cryptomycota as a basal branch or sister group to the fungi. Microsporidia can be transmitted by food and water and are likely zoonotic, as they parasitize a wide range of invertebrate and vertebrate hosts. Infection in humans occurs in both immunocompetent and immunodeficient hosts, e.g., in patients with organ transplantation, patients with advanced human immunodeficiency virus (HIV) infection, and patients receiving immune modulatory therapy such as anti-tumor necrosis factor alpha antibody. Clusters of infections due to latent infection in transplanted organs have also been demonstrated. Gastrointestinal infection is the most common manifestation; however, microsporidia can infect virtually any organ system, and infection has resulted in keratitis, myositis, cholecystitis, sinusitis, and encephalitis. Both albendazole and fumagillin have efficacy for the treatment of various species of microsporidia; however, albendazole has limited efficacy for the treatment of Enterocytozoon bieneusi. In addition, immune restoration can lead to resolution of infection. While the prevalence rate of microsporidiosis in patients with AIDS has fallen in the United States, due to the widespread use of combination antiretroviral therapy (cART), infection continues to occur throughout the world and is still seen in the United States in the setting of cART if a low CD4 count persists.

Evolutionary Pathways and Trajectories in Antibiotic Resistance.

Abstract: Evolution is the hallmark of life. Descriptions of the evolution of microorganisms have provided a wealth of information, but knowledge regarding "what happened" has precluded a deeper understanding of "how" evolution has proceeded, as in the case of antimicrobial resistance. The difficulty in answering the "how" question lies in the multihierarchical dimensions of evolutionary processes, nested in complex networks, encompassing all units of selection, from genes to communities and ecosystems. At the simplest ontological level (as resistance genes), evolution proceeds by random (mutation and drift) and directional (natural selection) processes; however, sequential pathways of adaptive variation can occasionally be observed, and under fixed circumstances (particular fitness landscapes), evolution is predictable. At the highest level (such as that of plasmids, clones, species, microbiotas), the systems' degrees of freedom increase dramatically, related to the variable dispersal, fragmentation, relatedness, or coalescence of bacterial populations, depending on heterogeneous and changing niches and selective gradients in complex environments. Evolutionary trajectories of antibiotic resistance find their way in these changing landscapes subjected to random variations, becoming highly entropic and therefore unpredictable. However, experimental, phylogenetic, and ecogenetic analyses reveal preferential frequented paths (highways) where antibiotic resistance flows and propagates, allowing some understanding of evolutionary dynamics, modeling and designing interventions. Studies on antibiotic resistance have an applied aspect in improving individual health, One Health, and Global Health, as well as an academic value for understanding evolution. Most importantly, they have a heuristic significance as a model to reduce the negative influence of anthropogenic effects on the environment.

SARS-CoV-2 Antiviral Therapy.

Abstract: The development of effective antiviral therapy for COVID-19 is critical for those awaiting vaccination, as well as for those who do not respond robustly to vaccination. This review summarizes 1 year of progress in the race to develop antiviral therapies for COVID-19, including research spanning preclinical and clinical drug development efforts, with an emphasis on antiviral compounds that are in clinical development or that are high priorities for clinical development. The review is divided into sections on compounds that inhibit SARS-CoV-2 enzymes, including its polymerase and proteases; compounds that inhibit virus entry, including monoclonal antibodies; interferons; and repurposed drugs that inhibit host processes required for SARS-CoV-2 replication. The review concludes with a summary of the lessons to be learned from SARS-CoV-2 drug development efforts and the challenges to continued progress.

Pathogenesis of Respiratory Viral and Fungal Coinfections.

Abstract: Individuals suffering from severe viral respiratory tract infections have recently emerged as "at risk" groups for developing invasive fungal infections. Influenza virus is one of the most common causes of acute lower respiratory tract infections worldwide. Fungal infections complicating influenza pneumonia are associated with increased disease severity and mortality, with invasive pulmonary aspergillosis being the most common manifestation. Strikingly, similar observations have been made during the current coronavirus disease 2019 (COVID-19) pandemic. The copathogenesis of respiratory viral and fungal coinfections is complex and involves a dynamic interplay between the host immune defenses and the virulence of the microbes involved that often results in failure to return to homeostasis. In this review, we discuss the main mechanisms underlying susceptibility to invasive fungal disease following respiratory viral infections. A comprehensive understanding of these interactions will aid the development of therapeutic modalities against newly identified targets to prevent and treat these emerging coinfections.

Giardia duodenalis: Biology and Pathogenesis.

Abstract: Giardia duodenalis captured the attention of Leeuwenhoek in 1681 while he was examining his own diarrheal stool, but, ironically, it did not really gain attention as a human pathogen until the 1960s, when outbreaks were reported. Key technological advances, including in vitro cultivation, genomic and proteomic databases, and advances in microscopic and molecular approaches, have led to an understanding that this is a eukaryotic organism with a reduced genome rather than a truly premitochondriate eukaryote. This has included the discovery of mitosomes (vestiges of mitochondria), a transport system with many of the features of the Golgi apparatus, and even evidence for a sexual or parasexual cycle. Cell biology approaches have led to a better understanding of how Giardia survives with two nuclei and how it goes through its life cycle as a noninvasive organism in the hostile environment of the lumen of the host intestine. Studies of its immunology and pathogenesis have moved past the general understanding of the importance of the antibody response in controlling infection to determining the key role of the Th17 response. This work has led to understanding of the requirement for a balanced host immune response that avoids the extremes of an excessive response with collateral damage or one that is unable to clear the organism. This understanding is especially important in view of the remarkable ranges of early manifestations, which range from asymptomatic to persistent diarrhea and weight loss, and longer-term sequelae that include growth stunting in children who had no obvious symptoms and a high frequency of postinfectious irritable bowel syndrome (IBS).

Understanding the Impact of Resistance to Influenza Antivirals

Abstract: SUMMARYInfluenza poses a significant burden on society and health care systems Although antivirals are an integral tool in effective influenza management, the potential for the emergence of antiviral-resistant viruses can lead to uncertainty and hesitation among front-line prescribers and policy makers Here, we provide an overview of influenza antiviral resistance in context, exploring the key concepts underlying its development and clinical impact Due to the acute nature of influenza in immunocompetent patients, resistant viruses that develop during antiviral treatment of a single patient ("treatment-emergent resistance") are usually cleared in a relatively short time, with no impact on future antiviral efficacy In addition, although available data are limited by small numbers of patients, they show that antiviral treatment still provides clinical benefit to the patient within whom resistance emerges In contrast, the sustained community transmission of resistant variants in the absence of treatment ("acquired resistance") is of greater concern and can potentially render front-line antivirals ineffective Importantly, however, resistant viruses are usually associated with reduced fitness such that their widespread transmission is relatively rare Influenza antivirals are an essential part of effective influenza management due to their ability to reduce the risk of complications and death in infected patients Although antiviral resistance should be taken seriously and requires continuous careful monitoring, it is not comparable to antibiotic resistance in bacteria, which can become permanent and widespread, with far-reaching medical consequences The benefits of antiviral treatment far outweigh concerns of potential resistance, which in the vast majority of cases does not have a significant clinical impact

Klebsiella oxytoca Complex: Update on Taxonomy, Antimicrobial Resistance, and Virulence.

Abstract: Klebsiella oxytoca is actually a complex of nine species-Klebsiella grimontii, Klebsiella huaxiensis, Klebsiella michiganensis, K. oxytoca, Klebsiella pasteurii, Klebsiella spallanzanii, and three unnamed novel species. Phenotypic tests can assign isolates to the complex, but precise species identification requires genome-based analysis. The K. oxytoca complex is a human commensal but also an opportunistic pathogen causing various infections, such as antibiotic-associated hemorrhagic colitis (AAHC), urinary tract infection, and bacteremia, and has caused outbreaks. Production of the cytotoxins tilivalline and tilimycin lead to AAHC, while many virulence factors seen in Klebsiella pneumoniae, such as capsular polysaccharides and fimbriae, have been found in the complex; however, their association with pathogenicity remains unclear. Among the 5,724 K. oxytoca clinical isolates in the SENTRY surveillance system, the rates of nonsusceptibility to carbapenems, ceftriaxone, ciprofloxacin, colistin, and tigecycline were 1.8%, 12.5%, 7.1%, 0.8%, and 0.1%, respectively. Resistance to carbapenems is increasing alarmingly. In addition to the intrinsic blaOXY, many genes encoding β-lactamases with varying spectra of hydrolysis, including extended-spectrum β-lactamases, such as a few CTX-M variants and several TEM and SHV variants, have been found. blaKPC-2 is the most common carbapenemase gene found in the complex and is mainly seen on IncN or IncF plasmids. Due to the ability to acquire antimicrobial resistance and the carriage of multiple virulence genes, the K. oxytoca complex has the potential to become a major threat to human health.

Erratum for Yahav et al., "New β-Lactam-β-Lactamase Inhibitor Combinations".

Abstract: Volume 34, no. 1, e00115-20, 2021, [https://doi.org/10.1128/CMR.00115-20][1]. Page 12, Table 4, “IMI-REL” column entry corresponding to Klebsiella pneumoniae, carbapenem resistant, n = 295, Greece (212): “8.0 b ” should read “98.0 b .” Page 12, Table 4, “IMI-REL” column entry

Staphylococcus aureus in Agriculture: Lessons in Evolution from a Multispecies Pathogen.

Abstract: SUMMARY Staphylococcus aureus is a formidable bacterial pathogen that is responsible for infections in humans and various species of wild, companion, and agricultural animals The ability of S aureus to move between humans and livestock is due to specific characteristics of this bacterium as well as modern agricultural practices Pathoadaptive clonal lineages of S aureus have emerged and caused significant economic losses in the agricultural sector While humans appear to be a primary reservoir for S aureus, the continued expansion of the livestock industry, globalization, and ubiquitous use of antibiotics has increased the dissemination of pathoadaptive S aureus in this environment This review comprehensively summarizes the available literature on the epidemiology, pathophysiology, genomics, antibiotic resistance (ABR), and clinical manifestations of S aureus infections in domesticated livestock The availability of S aureus whole-genome sequence data has provided insight into the mechanisms of host adaptation and host specificity Several lineages of S aureus are specifically adapted to a narrow host range on a short evolutionary time scale However, on a longer evolutionary time scale, host-specific S aureus has jumped the species barrier between livestock and humans in both directions several times S aureus illustrates how close contact between humans and animals in high-density environments can drive evolution The use of antibiotics in agriculture also drives the emergence of antibiotic-resistant strains, making the possible emergence of human-adapted ABR strains from agricultural practices concerning Addressing the concerns of ABR S aureus, without negatively affecting agricultural productivity, is a challenging priority

Type I Natural Killer T Cells as Key Regulators of the Immune Response to Infectious Diseases.

Abstract: SUMMARY The immune system must work in an orchestrated way to achieve an optimal response upon detection of antigens. The cells comprising the immune response are traditionally divided into two major subsets, innate and adaptive, with particular characteristics for each type. Type I natural killer T (iNKT) cells are defined as innate-like T cells sharing features with both traditional adaptive and innate cells, such as the expression of an invariant T cell receptor (TCR) and several NK receptors. The invariant TCR in iNKT cells interacts with CD1d, a major histocompatibility complex class I (MHC-I)-like molecule. CD1d can bind and present antigens of lipid nature and induce the activation of iNKT cells, leading to the secretion of various cytokines, such as gamma interferon (IFN-γ) and interleukin 4 (IL-4). These cytokines will aid in the activation of other immune cells following stimulation of iNKT cells. Several molecules with the capacity to bind to CD1d have been discovered, including α-galactosylceramide. Likewise, several molecules have been synthesized that are capable of polarizing iNKT cells into different profiles, either pro- or anti-inflammatory. This versatility allows NKT cells to either aid or impair the clearance of pathogens or to even control or increase the symptoms associated with pathogenic infections. Such diverse contributions of NKT cells to infectious diseases are supported by several publications showing either a beneficial or detrimental role of these cells during diseases. In this article, we discuss current data relative to iNKT cells and their features, with an emphasis on their driving role in diseases produced by pathogenic agents in an organ-oriented fashion.

Echinococcoses in Iran, Turkey, and Pakistan: Old Diseases in the New Millennium.

Abstract: Echinococcosis is considered a cosmopolitan zoonosis caused by different species of small taeniid tapeworms of the genus Echinococcus and is regarded as a neglected zoonosis. Cystic and alveolar echinococcoses are endemic diseases of Tibetan, Pamir, and Iranian plateaus. All of the countries within the Iranian plateau are affected by echinococcosis. Pakistan, Turkey, and Iran are the three most populous countries of the region, in which echinococcosis is highly endemic. The three neighboring countries share strong cultural and socioeconomic ties. The present study aimed to provide a broad review of the status of cystic and alveolar echinococcosis, summarizing the current knowledge about geographical distribution, molecular epidemiology, and transmission dynamics of Echinococcus granulosus sensu lato and Echinococcus multilocularis in this region. Additionally, we aimed to understand disease burden and risk factors as basic requirements for establishing a surveillance system and planning prevention and control programs. A considerable body of information is available on different aspects of echinococcosis in this region; however, several information and research gaps need to be filled before planning control programs. None of the countries in the region have an elaborate echinococcosis control program. Effective control programs require multi/intersectoral coordination within a One Health approach with a long-term political and administrative commitment and enhanced international collaboration among the three countries.

Canine and Feline Parasitology: Analogies, Differences, and Relevance for Human Health.

Abstract: Cats and dogs are treated as family members by most pet owners. Therefore, a high quality of veterinary care and preventive medicine is imperative for animal health and welfare and for the protection of humans from zoonotic pathogens. There is a general perception of cats being treated as "small dogs," especially in the field of clinical parasitology. As a result, several important differences between the two animal species are not taken into proper consideration and are often overlooked. Dogs and cats are profoundly different under evolutionary, biological, ethological, behavioral, and immunological standpoints. These differences impact clinical features, diagnosis, and control of canine and feline parasites and transmission risk for humans. This review outlines the most common parasitoses and vector-borne diseases of dogs and cats, with a focus on major convergences and divergences, and discusses parasites that have (i) evolved based on different preys for dogs and cats, (ii) adapted due to different immunological or behavioral animal profiles, and (iii) developed more similarities than differences in canine and feline infections and associated diseases. Differences, similarities, and peculiarities of canine and feline parasitology are herein reviewed in three macrosections: (i) carnivorism, vegetarianism, anatomy, genetics, and parasites, (ii) evolutionary adaptation of nematodes, including veterinary reconsideration and zoonotic importance, and (iii) behavior and immune system driving ectoparasites and transmitted diseases. Emphasis is given to provide further steps toward a more accurate evaluation of canine and feline parasitology in a changing world in terms of public health relevance and One Health approach.

Interplay between Candida albicans and Lactic Acid Bacteria in the Gastrointestinal Tract: Impact on Colonization Resistance, Microbial Carriage, Opportunistic Infection, and Host Immunity.

Abstract: Emerging studies have highlighted the disproportionate role of Candida albicans in influencing both early community assembly of the bacterial microbiome and dysbiosis during allergic diseases and intestinal inflammation. Nonpathogenic colonization of the human gastrointestinal (GI) tract by C. albicans is common, and the role of this single fungal species in modulating bacterial community reassembly after broad-spectrum antibiotics can be readily recapitulated in mouse studies. One of the most notable features of C. albicans-associated dysbiotic states is a marked change in the levels of lactic acid bacteria (LAB). C. albicans and LAB share metabolic niches throughout the GI tract, and in vitro studies have identified various interactions between these microbes. The two predominant LAB affected are Lactobacillus species and Enterococcus species. Lactobacilli can antagonize enterococci and C. albicans, while Enterococcus faecalis and C. albicans have been reported to exhibit a mutualistic relationship. E. faecalis and C. albicans are also causative agents of a variety of life-threatening infections, are frequently isolated together from mixed-species infections, and share certain similarities in clinical presentation-most notably their emergence as opportunistic pathogens following disruption of the microbiota. In this review, we discuss and model the mechanisms used by Lactobacillus species, E. faecalis, and C. albicans to modulate each other's growth and virulence in the GI tract. With multidrug-resistant E. faecalis and C. albicans strains becoming increasingly common in hospital settings, examining the interplay between these three microbes may provide novel insights for enhancing the efficacy of existing antimicrobial therapies.

Laboratory Diagnosis of Lyme Borreliosis.

Abstract: Lyme borreliosis is caused by a growing list of related, yet distinct, spirochetes with complex biology and sophisticated immune evasion mechanisms. It may result in a range of clinical manifestations involving different organ systems, and can lead to persistent sequelae in a subset of cases. The pathogenesis of Lyme borreliosis is incompletely understood, and laboratory diagnosis, the focus of this review, requires considerable understanding to interpret the results correctly. Direct detection of the infectious agent is usually not possible or practical, necessitating a continued reliance on serologic testing. Still, some important advances have been made in the area of diagnostics, and there are many promising ideas for future assay development. This review summarizes the state of the art in laboratory diagnostics for Lyme borreliosis, provides guidance in test selection and interpretation, and highlights future directions.

Practical Guidance for Clinical Microbiology Laboratories: Diagnosis of Ocular Infections.

Abstract: The variety and complexity of ocular infections have increased significantly in the last decade since the publication of Cumitech 13B, Laboratory Diagnosis of Ocular Infections (L. D. Gray, P. H. Gilligan, and W. C. Fowler, Cumitech 13B, Laboratory Diagnosis of Ocular Infections, 2010). The purpose of this practical guidance document is to review, for individuals working in clinical microbiology laboratories, current tools used in the laboratory diagnosis of ocular infections. This document begins by describing the complex, delicate anatomy of the eye, which often leads to limitations in specimen quantity, requiring a close working bond between laboratorians and ophthalmologists to ensure high-quality diagnostic care. Descriptions are provided of common ocular infections in developed nations and neglected ocular infections seen in developing nations. Subsequently, preanalytic, analytic, and postanalytic aspects of laboratory diagnosis and antimicrobial susceptibility testing are explored in depth.

Invasive Haemophilus influenzae Infections after 3 Decades of Hib Protein Conjugate Vaccine Use.

Abstract: Haemophilus influenzae serotype b (Hib) was previously the most common cause of bacterial meningitis and an important etiologic agent of pneumonia in children aged <5 years. Its major virulence factor is the polyribosyl ribitol phosphate (PRP) polysaccharide capsule. In the 1980s, PRP-protein conjugate Hib vaccines were developed and are now included in almost all national immunization programs, achieving a sustained decline in invasive Hib infections. However, invasive Hib disease has not yet been eliminated in countries with low vaccine coverage, and sporadic outbreaks of Hib infection still occur occasionally in countries with high vaccine coverage. Over the past 2 decades, other capsulated serotypes have been recognized increasingly as causing invasive infections. H. influenzae serotype a (Hia) is now a major cause of invasive infection in Indigenous communities of North America, prompting a possible requirement for an Hia conjugate vaccine. H. influenzae serotypes e and f are now more common than serotype b in Europe. Significant year-to-year increases in nontypeable H. influenzae invasive infections have occurred in many regions of the world. Invasive H. influenzae infections are now seen predominantly in patients at the extremes of life and those with underlying comorbidities. This review provides a comprehensive and critical overview of the current global epidemiology of invasive H. influenzae infections in different geographic regions of the world. It discusses those now at risk of invasive Hib disease, describes the emergence of other severe invasive H. influenzae infections, and emphasizes the importance of long-term, comprehensive, clinical and microbiologic surveillance to monitor a vaccine's impact.

The Five Ds of Outpatient Antibiotic Stewardship for Urinary Tract Infections.

Abstract: Urinary tract infections (UTI) are one of the most common indications for antibiotic prescriptions in the outpatient setting. Given rising rates of antibiotic resistance among uropathogens, antibiotic stewardship is critically needed to improve outpatient antibiotic use, including in outpatient clinics (primary care and specialty clinics) and emergency departments. Outpatient clinics are in general a neglected practice area in antibiotic stewardship programs, yet most antibiotic use in the United States is in the outpatient setting. This article provides a comprehensive review of antibiotic stewardship strategies for outpatient UTI in the adult population, with a focus on the "five Ds" of stewardship for UTI, including right diagnosis, right drug, right dose, right duration, and de-escalation. Stewardship interventions that have shown success for improving prescribing for outpatient UTI are discussed, including diagnostic stewardship strategies, such as reflex urine cultures, computerized decision support systems, and modified reporting of urine culture results. Among the many challenges to achieving stewardship for UTI in the outpatient setting, some of the most important are diagnostic uncertainty, increasing antibiotic resistance, limitations of guidelines, and time constraints of stewardship personnel and front-line providers. This article presents a stewardship framework, built on current evidence and expert opinion, that clinicians can use to guide their own outpatient management of UTI.

Erratum: SARS-CoV-2 and health care worker protection in low-risk settings: a review of modes of transmission and a novel airborne model involving inhalable particles (Clin Microbiol Rev, (2021) 34(1), e00184-20, 10.1128/CMR.00184-20)

Abstract: Volume 34, no 1, e00184-20, 2021, https://doi org/10 1128/CMR 00184-20 Page 9, last sentence of second paragraph of the “Epidemiological Studies on Transmission” subsection: “basic PCI measures beyond PPE” should read “basic IPC measures beyond PPE ” Page 26: Reference 99 should appear as shown below 99 Park BJ, Peck AJ, Kuehnert MJ, Newbern C, Smelser C, Comer JA, Jernigan D, McDonald LC 2004 Lack of SARS transmission among healthcare workers, United States Emerg Infect Dis 10:244–248 https://doi org/10 3201/eid1002 030793 © 2021 American Society for Microbiology All Rights Reserved

Intestinal Bacteriophage Therapy: Looking for Optimal Efficacy.

Abstract: Several human intestinal microbiota studies suggest that bacteriophages, viruses infecting bacteria, play a role in gut homeostasis. Currently, bacteriophages are considered a tool to precisely engineer the intestinal microbiota, but they have also attracted considerable attention as a possible solution to fight against bacterial pathogens resistant to antibiotics. These two applications necessitate bacteriophages to reach and kill their bacterial target within the gut environment. Unfortunately, exploitable clinical data in this field are scarce. Here, we review the administration of bacteriophages to target intestinal bacteria in mammalian experimental models. While bacteriophage amplification in the gut was often confirmed, we found that in most studies, it had no significant impact on the load of the targeted bacteria. In particular, we observed that the outcome of bacteriophage treatments is linked to the behavior of the target bacteria toward each animal model. Treatment efficacy ranges from poor in asymptomatic intestinal carriage to high in intestinal disease. This broad range of efficacy underlines the difficulties to reach a consensus on the impact of bacteriophages in the gut and calls for deeper investigations of key parameters that influence the success of such interventions before launching clinical trials.

Aspergillus terreus Species Complex.

Abstract: Infections due to Aspergillus species are an acute threat to human health; members of the Aspergillus section Fumigati are the most frequently occurring agents, but depending on the local epidemiology, representatives of section Terrei or section Flavi are the second or third most important. Aspergillus terreus species complex is of great interest, as it is usually amphotericin B resistant and displays notable differences in immune interactions in comparison to Aspergillus fumigatus. The latest epidemiological surveys show an increased incidence of A. terreus as well as an expanding clinical spectrum (chronic infections) and new groups of at-risk patients being affected. Hallmarks of these non-Aspergillus fumigatus invasive mold infections are high potential for tissue invasion, dissemination, and possible morbidity due to mycotoxin production. We seek to review the microbiology, epidemiology, and pathogenesis of A. terreus species complex, address clinical characteristics, and highlight the underlying mechanisms of amphotericin B resistance. Selected topics will contrast key elements of A. terreus with A. fumigatus. We provide a comprehensive resource for clinicians dealing with fungal infections and researchers working on A. terreus pathogenesis, aiming to bridge the emerging translational knowledge and future therapeutic challenges on this opportunistic pathogen.