Tuberculosis (TB) still poses a major threat to mankind and during the last thirty years we have seen a recrudescence of the disease even in countries where TB was thought to be conquered. It is common opinion that more effective control tools such as new diagnostics, a new vaccine and new drugs are urgently needed to control the global pandemic, though the so far insufficient understanding of the Mycobacterium tuberculosis (Mtb) mechanism of pathogenesis is a major obstacle for the development of these control tools. In this review, we will summarize the recent advancement in the understanding of Mtb biology and on the pathogenesis of Mtb infection with emphasis on latent infection, with the change in paradigm of the last few years where the dichotomy between latent and active disease has been reconsidered in favor of a dynamic equilibrium between the host and the bacilli, encompassing a continuous spectrum of conditions that has been named TB spectrum. Implications for the diagnosis and control of disease in certain population will also be discussed.

The role and function of PE_PGRS proteins of Mycobacterium tuberculosis (Mtb) remains elusive. In this study for the first time, Mtb isogenic mutants missing selected PE_PGRSs were used to investigate their role in the pathogenesis of tuberculosis (TB). We demonstrate that the MtbΔPE_PGRS30 mutant was impaired in its ability to colonize lung tissue and to cause tissue damage, specifically during the chronic steps of infection. Inactivation of PE_PGRS30 resulted in an attenuated phenotype in murine and human macrophages due to the inability of the Mtb mutant to inhibit phagosome–lysosome fusion. Using a series of functional deletion mutants of PE_PGRS30 to complement MtbΔPE_PGRS30, we show that the unique C-terminal domain of the protein is not required for the full virulence. Interestingly, when Mycobacterium smegmatis recombinant strain expressing PE_PGRS30 was used to infect macrophages or mice in vivo, we observed enhanced cytotoxicity and cell death, and this effect was dependent upon the PGRS domain of the protein.Taken together these results indicate that PE_PGRS30 is necessary for the full virulence of Mtb and sufficient to induce cell death in host cells by the otherwise non-pathogenic species M. smegmatis, clearly demonstrating that PE_PGRS30 is an Mtb virulence factor.

Extended-spectrum-β-lactamase (ESBL)-producing strains of Escherichia coli are a significant cause of bloodstream infections (BSI) in hospitalized and nonhospitalized patients. We previously showed that delaying effective antimicrobial therapy in BSI caused by ESBL producers significantly increases mortality. The aim of this retrospective 7-year analysis was to identify risk factors for inadequate initial antimicrobial therapy (IIAT) (i.e., empirical treatment based on a drug to which the isolate had displayed in vitro resistance) for inpatients with BSI caused by ESBL-producing E. coli . Of the 129 patients considered, 56 (43.4%) received IIAT for 48 to 120 h (mean, 72 h). Independent risk factors for IIAT include an unknown BSI source (odds ratios [OR], 4.86; 95% confidence interval [CI], 1.98 to 11.91; P = 0.001), isolate coresistance to ≥3 antimicrobials (OR, 3.73; 95% CI, 1.58 to 8.83; P = 0.003), hospitalization during the 12 months preceding BSI onset (OR, 3.33; 95% CI, 1.42 to 7.79; P = 0.005), and antimicrobial therapy during the 3 months preceding BSI onset (OR, 2.65; 95% CI, 1.11 to 6.29; P = 0.02). IIAT was the strongest risk factor for 21-day mortality and significantly increased the length of hospitalization after BSI onset. Our results underscore the need for a systematic approach to the management of patients with serious infections by ESBL-producing E. coli . Such an approach should be based on sound, updated knowledge of local infectious-disease epidemiology, detailed analysis of the patient's history with emphasis on recent contact with the health care system, and aggressive attempts to identify the infectious focus that has given rise to the BSI.

We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that bronchoalveolar lavage fluid (BALF) macrophage clusters FCN1⁺ and FCN1⁺SPP1⁺ predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48^hiS100A12⁺ and CD48⁺SPP1⁺ that drive rheumatoid arthritis (RA) synovitis. BALF macrophage cluster FABP4⁺ predominant in healthy lung was transcriptionally related to STM cluster TREM2⁺ that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and they remained high in the post–COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared with other causes of severe pneumonia, and IHC localized SPP1⁺ macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives proinflammatory activation of CD14⁺ monocytes and development of PD-L1⁺ neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post–COVID-19 pathology.

Human papillomavirus 16 infection has been proven to be associated with oropharyngeal squamous cell carcinomas (SCCs) and is probably the main reason of the reported increase in the incidence. The role of high-risk (HR) HPV for carcinogenesis of other sites in the head and neck awaits confirmation. With the aim to evaluate the prevalence of HPV infection and the reliability of different diagnostic tools in SCCs of different sites, 109 consecutive untreated head and neck SCCs were enroled, and fresh tumour samples collected. Human papillomavirus DNA was detected by Digene Hybrid Capture 2 (HC2). Human papillomavirus E6 and E7 mRNA were detected by NucliSENS EasyQ HPVv1. P16 expression was evaluated by immunohistochemistry. In all, 12.84% of cases were infected by HR genotypes and 1.84% by low-risk genotypes. Human papillomavirus 16 accounted for 87% of HR infections. The overall agreement between DNA and RNA detection is 99.1%. Although p16 expression clearly correlates with HPV infection (P=0.0051), the inter-rater agreement is poor (k=0.27). The oropharynx showed the highest HR HPV infection rate (47.6%) and was also the only site in which p16 immunohistochemistry revealed to be a fair, but not excellent, diagnostic assay (κ=0.61). The prognostic role of HR HPV infection in oropharyngeal oncology, with its potential clinical applications, underscores the need for a consensus on the most appropriate detection methods. The present results suggest that viral mRNA detection could be the standard for fresh samples, whereas DNA detection could be routinely used in formalin-fixed, paraffin-embedded samples.