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- Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanidPublication . Bateson, Anna; Canseco, Julio Ortiz; McHugh, Timothy D.; Witney, Adam A.; Feuerriegel, Silke; Merker, Matthias; Kohl, Thomas A.; Utpatel, Christian; Niemann, Stefan; Andres, Sonke; Kranzer, Katharina; Maurer, Florian P.; Ghodousi, Arash; Borroni, Emanuele; Cirillo, Daniela Maria; Wijkander, Maria; Toro, Juan C.; Groenheit, Ramona; Werngren, Jim; Machado, Diana; Viveiros, Miguel; Warren, Robin M.; Sirgel, Frederick; Dippenaar, Anzaan; Koeser, Claudio U.; Sun, Eugene; Timm, Juliano; Instituto de Higiene e Medicina Tropical (IHMT); Global Health and Tropical Medicine (GHTM); TB, HIV and opportunistic diseases and pathogens (THOP); British Society for Antimicrobial Chemotherapy | Oxford University PressObjectives: To develop a robust phenotypic antimicrobial susceptibility testing (AST) method with a correctly set breakpoint for pretomanid (Pa), the most recently approved anti-tuberculosis drug. Methods: The Becton Dickinson Mycobacterial Growth Indicator Tube™ (MGIT) system was used at six laboratories to determine the MICs of a phylogenetically diverse collection of 356 Mycobacterium tuberculosis complex (MTBC) strains to establish the epidemiological cut-off value for pretomanid. MICs were correlated with WGS data to study the genetic basis of differences in the susceptibility to pretomanid. Results: We observed ancient differences in the susceptibility to pretomanid among various members of MTBC. Most notably, lineage 1 of M. tuberculosis, which is estimated to account for 28% of tuberculosis cases globally, was less susceptible than lineages 2, 3, 4 and 7 of M. tuberculosis, resulting in a 99th percentile of 2 mg/L for lineage 1 compared with 0.5 mg/L for the remaining M. tuberculosis lineages. Moreover, we observed that higher MICs (≥8 mg/L), which probably confer resistance, had recently evolved independently in six different M. tuberculosis strains. Unlike the aforementioned ancient differences in susceptibility, these recent differences were likely caused by mutations in the known pretomanid resistance genes. Conclusions: In light of these findings, the provisional critical concentration of 1 mg/L for MGIT set by EMA must be re-evaluated. More broadly, these findings underline the importance of considering the global diversity of MTBC during clinical development of drugs and when defining breakpoints for AST.
- Readdressing the genetic diversity and taxonomy of the Mesoniviridae family, as well as its relationships with other nidoviruses and putative mesonivirus-like viral sequencesPublication . Morais, Paulo; Trovão, Nídia S; Abecasis, Ana B; Parreira, Ricardo; Instituto de Higiene e Medicina Tropical (IHMT); TB, HIV and opportunistic diseases and pathogens (THOP); Global Health and Tropical Medicine (GHTM); Vector borne diseases and pathogens (VBD); ElsevierResearch on the recently established Mesoniviridae family (Order Nidovirales), RNA genome insect-specific viruses, has been steadily growing in the last decade. However, after the last detailed phylogenetic characterization of mesoniviruses in 2014, numerous new sequences, even in organisms other than mosquitos, have been identified and characterized. In this study, we analyzed nucleotide and protein sequences of mesoniviruses with a wide range of molecular tools including genetic distance, Shannon entropy, selective pressure analysis, polymorphism identification, principal coordinate analysis, likelihood mapping and phylodynamic reconstruction. We also sought to revaluate new mesoniviruses sequence positions within the family, proposing a taxonomic revision. The different sub-lineages of mosquito mesoniviruses sequences presented low sequence diversity and entropy, with incongruences to the existing taxonomy being found after an extensive phylogenetic characterization. High sequence discrepancy and differences in genome organization were found between mosquito mesoniviruses and other mesoniviruses, so their future classification, as other meso-like viruses that are found in other organisms, should be approached with caution. No evidence of frequent recombination was found, and mesonivirus genomes seem to evolve under strong purifying selection. Insufficient data by root-to-tip analysis did not yet allow for an adequate phylogeographic reconstruction.
- Changes to virus taxonomy and to the International Code of Virus Classification and Nomenclature ratified by the International Committee on Taxonomy of Viruses (2021)Publication . Walker, Peter J.; Siddell, Stuart G.; Lefkowitz, Elliot J.; Mushegian, Arcady R.; Adriaenssens, Evelien M.; Alfenas-Zerbini, Poliane; Davison, Andrew J.; Dempsey, Donald M.; Dutilh, Bas E.; García, María Laura; Harrach, Balázs; Harrison, Robert L.; Hendrickson, R. Curtis; Junglen, Sandra; Knowles, Nick J.; Krupovic, Mart; Kuhn, Jens H.; Lambert, Amy J.; Łobocka, Małgorzata; Nibert, Max L.; Oksanen, Hanna M.; Orton, Richard J.; Robertson, David L.; Rubino, Luisa; Sabanadzovic, Sead; Simmonds, Peter; Smith, Donald B.; Suzuki, Nobuhiro; Van Dooerslaer, Koenraad; Vandamme, Anne Mieke; Varsani, Arvind; Zerbini, Francisco Murilo; Instituto de Higiene e Medicina Tropical (IHMT); Global Health and Tropical Medicine (GHTM); TB, HIV and opportunistic diseases and pathogens (THOP); Springer Science Business MediaThis article reports the changes to virus taxonomy approved and ratified by the International Committee on Taxonomy of Viruses (ICTV) in March 2021. The entire ICTV was invited to vote on 290 taxonomic proposals approved by the ICTV Executive Committee at its meeting in October 2020, as well as on the proposed revision of the International Code of Virus Classification and Nomenclature (ICVCN). All proposals and the revision were ratified by an absolute majority of the ICTV members. Of note, ICTV mandated a uniform rule for virus species naming, which will follow the binomial 'genus-species' format with or without Latinized species epithets. The Study Groups are requested to convert all previously established species names to the new format. ICTV has also abolished the notion of a type species, i.e., a species chosen to serve as a name-bearing type of a virus genus. The remit of ICTV has been clarified through an official definition of ‘virus’ and several other types of mobile genetic elements. The ICVCN and ICTV Statutes have been amended to reflect these changes.
- Causes of multidrug-resistant tuberculosis from the perspectives of health providers:Publication . Souza, Ludmilla Leidianne Limirio; Santos, Felipe Lima dos; Crispim, Juliane de Almeida; Fiorati, Regina Célia; Dias, Sónia; Bruce, Alexandre Tadashi Inomata; Alves, Yan Mathias; Ramos, Antônio Carlos Vieira; Berra, Thaís Zamboni; da Costa, Fernanda Bruzadelli Paulino; Alves, Luana Seles; Monroe, Aline Aparecida; Fronteira, Inês; Arcêncio, Ricardo Alexandre; Escola Nacional de Saúde Pública (ENSP); Population health, policies and services (PPS); Instituto de Higiene e Medicina Tropical (IHMT); Global Health and Tropical Medicine (GHTM); BioMed Central (BMC)Background: Multidrug-resistant tuberculosis (MDR-TB) is a serious phenomenon on a global scale that can worsen with the COVID-19 pandemic. The study aimed to understand the perceptions of health professionals about MDR-TB, their strategies to ensure adherence to treatment and their challenges in the context of the COVID-19 pandemic in a priority municipality for disease control. Methods: We conducted a qualitative study and recruited 14 health providers (four doctors, three nurses, three nursing technicians, three nursing assistants and a social worker) working in a city in the state of São Paulo, Brazil. Remote semi-structured interviews were conducted with the participants. For data analysis, the thematic content analysis technique was applied according to the study’s theoretical framework. Results: The study revealed the causes of MDR-TB are associated with poverty, vulnerability, and social risk. A pre-judgement from the providers was observed, namely, all patients do not adhere due their resistance and association with drug abuse or alcoholism. The study also observed difficulty among health providers in helping patients reconstruct and reframe their life projects under a care perspective, which would strengthen adherence. Other issues that weakened adherence were the cuts in social protection and the benefits really necessary to the patients and a challenge for the providers manage that. The participants revealed that their actions were impacted by the pandemic and insecurity and fear manifested by patients after acquiring COVID-19. For alleviating this, medical appointments by telephone, delivery of medicine in the homes of patients and visits by health professionals once per week were provided. Conclusion: The study advances knowledge by highlighting the challenges faced by the health system with the adherence of patients with MDR-TB in a context aggravated by the pandemic. An improvement in DOT is really necessary to help the patients reframe their lives without prejudices, face their fears and insecurity, recover their self-esteem and motivate in concluding their treatment.
- Increase of cd4+cd25highfoxp3+ cells impairs in vitro human microbicidal activity against mycobacterium tuberculosis during latent and acute pulmonary tuberculosisPublication . Stringari, Lorenzzo Lyrio; Covre, Luciana Polaco; da Silva, Flávia Dias Coelho; de Oliveira, Vivian Leite; Campana, Maria Carolina; Hadad, David Jamil; Palaci, Moisés; Salgame, Padmini; Dietze, Reynaldo; Gomes, Daniel Cláudio de Oliveira; Ribeiro-Rodrigues, Rodrigo; Instituto de Higiene e Medicina Tropical (IHMT); Individual Health Care (IHC); Global Health and Tropical Medicine (GHTM); PLOS - Public Library of ScienceBackground Regulatory T cells (Tregs) play a critical role during Mycobacterium tuberculosis (Mtb) infection, modulating host responses while neutralizing excessive inflammation. However, their impact on regulating host protective immunity is not completely understood. Here, we demonstrate that Treg cells abrogate the in vitro microbicidal activity against Mtb. Methods We evaluated the in vitro microbicidal activity of peripheral blood mononuclear cells (PBMCs) from patients with active tuberculosis (TB), individuals with latent tuberculosis infection (LTBI, TST+/IGRA+) and healthy control (HC, TST-/IGRA-) volunteers. PBMCs, depleted or not of CD4+CD25+ T-cells, were analyzed to determine frequency and influence on microbicidal activity during in vitro Mtb infection with four clinical isolates (S1, S5, R3, and R6) and one reference strain (H37Rv). Results The frequency of CD4+CD25highFoxP3+ cells were significantly higher in Mtb infected whole blood cultures from both TB patients and LTBI individuals when compared to HC. Data from CD4+CD25+ T-cells depletion demonstrate that increase of CD4+CD25highFoxP3+ is associated with an impairment of Th-1 responses and a diminished in vitro microbicidal activity of LTBI and TB groups. Conclusions Tregs restrict host anti-mycobacterial immunity during active disease and latent infection and thereby may contribute to both disease progression and pathogen persistence.
- Genomic-based surveillance reveals high ongoing transmission of multi-drug-resistant Mycobacterium tuberculosis in Southern BrazilPublication . Salvato, Richard Steiner; Reis, Ana Júlia; Schiefelbein, Sun Hee; Gómez, Michael Andrés Abril; Salvato, Stéphanie Steiner; da Silva, Larissa Vitória; Costa, Elis Regina Dalla; Unis, Gisela; Dias, Claudia Fontoura; Viveiros, Miguel; Portugal, Isabel; von Groll, Andrea; da Silva, Pedro Eduardo Almeida; Kritski, Afrânio Lineu; Perdigão, João; Rossetti, Maria Lucia Rosa; TB, HIV and opportunistic diseases and pathogens (THOP); Instituto de Higiene e Medicina Tropical (IHMT); Global Health and Tropical Medicine (GHTM); ElsevierGenomic-based surveillance on the occurrence of drug resistance and its transmission dynamics has emerged as a powerful tool for the control of tuberculosis (TB). A whole-genome sequencing approach, phenotypic testing and clinical-epidemiological investigation were used to undertake a retrospective population-based study on drug-resistant (DR)-TB in Rio Grande do Sul, the largest state in Southern Brazil. The analysis included 305 resistant Mycobacterium tuberculosis strains sampled statewide from 2011 to 2014, and covered 75.7% of all DR-TB cases identified in this period. Lineage 4 was found to be predominant (99.3%), with high sublineage-level diversity composed mainly of 4.3.4.2 [Latin American and Mediterranean (LAM)/RD174], 4.3.3 (LAM/RD115) and 4.1.2.1 (Haarlem/RD182) sublineages. Genomic diversity was also reflected in resistance of the variants to first-line drugs. A large number of distinct resistance-conferring mutations, including variants that have not been reported previously in any other setting worldwide, and 22 isoniazid-monoresistant strains with mutations described as disputed in the rpoB gene but causing rifampicin resistance generally missed by automated phenotypic tests as BACTEC MGIT. Using a cut-off of five single nucleotide polymorphisms, the estimated recent transmission rate was 55.1%, with 168 strains grouped into 28 genomic clusters. The most worrying fact concerns multi-drug-resistant (MDR) strains, of which 73.4% were clustered. Different resistance profiles and acquisition of novel mutations intraclusters revealed important amplification of resistance in the region. This study described the diversity of M. tuberculosis strains, the basis of drug resistance, and ongoing transmission dynamics across the largest state in Southern Brazil, stressing the urgent need for MDR-TB transmission control state-wide.
- Molecular Epidemiology of Rotavirus Strains in Symptomatic and Asymptomatic Children in Manhiça District, Southern Mozambique 2008–2019Publication . Manjate, Filomena; João, Eva D.; Chirinda, Percina; Garrine, Marcelino; Vubil, Delfino; Nobela, Nélio; Kotloff, Karen; Nataro, James P.; Nhampossa, Tacilta; Acácio, Sozinho; Tate, Jacqueline E.; Parashar, Umesh; Mwenda, Jason M.; Alonso, Pedro L.; Nyaga, Martin; Cunha, Celso; Mandomando, Inácio; Global Health and Tropical Medicine (GHTM); Instituto de Higiene e Medicina Tropical (IHMT); TB, HIV and opportunistic diseases and pathogens (THOP); MDPI - Multidisciplinary Digital Publishing InstituteGroup A rotaviruses remain the leading cause of diarrhoea in children aged <5 years. Mozambique introduced rotavirus vaccine (Rotarix® ) in September 2015. We report rotavirus geno-types circulating among symptomatic and asymptomatic children in Manhiça District, Mozambique, pre-and post-vaccine introduction. Stool was collected from enrolled children and screened for ro-tavirus by enzyme-immuno-sorbent assay. Positive specimens were genotyped for VP7 (G genotypes) and VP4 (P genotypes) by the conventional reverse transcriptase polymerase chain reaction. The combination G12P[8] was more frequently observed in pre-vaccine than in post-vaccine introduction, in moderate to severe diarrhoea (34%, 61/177 vs. 0, p < 0.0001) and controls (23%, 26/113 vs. 0, p = 0.0013) and mixed genotypes (36%, 24/67 vs. 7% 4/58, p = 0.0003) in less severe diarrhoea. We observed changes in post-vaccine compared to pre-vaccine introduction, where G3P[4] and G3P[8] were prevalent in moderate to severe diarrhoea (10%, 5/49 vs. 0, p = 0.0002; and 14%, 7/49 vs. 1%, 1/177, p < 0.0001; respectively), and in less severe diarrhoea (21%, 12/58 vs. 0, p = 0.003; and 24%, 14/58 vs. 0, p < 0.0001; respectively). Our surveillance demonstrated the circulation of similar genotypes contemporaneously among cases and controls, as well as switching from pre-to post-vaccine introduction. Continuous surveillance is needed to evaluate the dynamics of the changes in genotypes following vaccine introduction.
- The neglected contribution of streptomycin to the tuberculosis drug resistance problemPublication . Rocha, Deisy M.G.C.; Viveiros, Miguel; Saraiva, Margarida; Osório, Nuno S.; TB, HIV and opportunistic diseases and pathogens (THOP); Instituto de Higiene e Medicina Tropical (IHMT); Global Health and Tropical Medicine (GHTM); Springer Science Business MediaThe airborne pathogen Mycobacterium tuberculosis is responsible for a present major public health problem worsened by the emergence of drug resistance. M. tuberculosis has acquired and developed streptomycin (STR) resistance mechanisms that have been maintained and transmitted in the population over the last decades. Indeed, STR resistant mutations are frequently identified across the main M. tuberculosis lineages that cause tuberculosis outbreaks worldwide. The spread of STR resistance is likely related to the low impact of the most frequent underlying mutations on the fitness of the bacteria. The withdrawal of STR from the first-line treatment of tuberculosis potentially lowered the importance of studying STR resistance. However, the prevalence of STR resistance remains very high, could be underestimated by current genotypic methods, and was found in outbreaks of multi-drug (MDR) and extensively drug (XDR) strains in different geographic regions. Therefore, the contribution of STR resistance to the problem of tuberculosis drug resistance should not be neglected. Here, we review the impact of STR resistance and detail well-known and novel candidate STR resistance mechanisms, genes, and mutations. In addition, we aim to provide insights into the possible role of STR resistance in the development of multi-drug resistant tuberculosis.
- Antibody response against selected epitopes in the HIV-1 envelope gp41 ectodomain contributes to reduce viral burden in HIV-1 infected patientsPublication . Marcelino, Rute; Gramacho, Filipa; Martin, Francisco; Brogueira, Pedro; Janeiro, Nuno; Afonso, Claudia; Badura, Robert; Valadas, Emília; Mansinho, Kamal; Caldeira, Luís; Taveira, Nuno; Marcelino, José M.; Instituto de Higiene e Medicina Tropical (IHMT); Global Health and Tropical Medicine (GHTM); TB, HIV and opportunistic diseases and pathogens (THOP); Individual Health Care (IHC); Nature Publishing GroupThe ectodomain of gp41 is the target of potent binding and neutralizing antibodies (NAbs) and is being explored in new strategies for antibody-based HIV vaccines. Previous studies have suggested that the W164A-3S (3S) and EC26-2A4 (EC26) peptides located in the gp41 ectodomain may be potential HIV vaccine candidates. We assessed 3S- and EC26-specific binding antibody responses and related neutralizing activity in a large panel of chronic HIV-1-infected Portuguese individuals on ART. A similar proportion of participants had antibodies binding to 3S (9.6%) and EC26 (9.9%) peptides but the level of reactivity against 3S was significantly higher compared to EC26, except in the rare patients with double peptide reactivity. The higher antigenicity of 3S was unrelated with disease stage, as assessed by CD4+ T cell counts, but it was directly related with plasma viral load. Most patients that were tested (89.9%, N = 268) showed tier 1 neutralizing activity, the potency being inversely associated with plasma viral load. In the subset of patients that were tested for neutralization of tier 2 isolates, neutralization breadth was inversely correlated with plasma viral load and directly correlated with CD4+ T cell counts. These results are consistent with a role for neutralizing antibodies in controlling viral replication and preventing the decline of CD4+ T lymphocytes. Importantly, in patients with 3S-specific antibodies, neutralizing titers were inversely correlated with viral RNA levels and proviral DNA levels. Moreover, patients with 3S and/or EC26-specific antibodies showed a 1.9-fold higher tier 2 neutralization score than patients without antibodies suggesting that 3S and/or EC26-specific antibodies contribute to neutralization breadth and potency in HIV-1 infected patients. Overall, these results suggest that antibodies targeting the S3 and EC26 epitopes may contribute to reduce viral burden and provide further support for the inclusion of 3S and EC26 epitopes in HIV-1 vaccine candidates.
- Proposal of Epidemiological Cutoff Values for Apramycin 15 μg and Florfenicol 30 μg Disks Applicable to Staphylococcus aureusPublication . Costa, Sofia Santos; Ferreira, Carolina; Ribeiro, Rute; Feßler, Andrea T; Schink, Anne-Kathrin; Kadlec, Kristina; Kaspar, Heike; Amaro, Ana; Albuquerque, Teresa; Abrantes, Patrícia; Morais, Catarina; Pomba, Constança; Schwarz, Stefan; Couto, Isabel; Instituto de Higiene e Medicina Tropical (IHMT); TB, HIV and opportunistic diseases and pathogens (THOP); Global Health and Tropical Medicine (GHTM); Mary Ann LeibertApramycin and florfenicol are two antimicrobial agents exclusively used in veterinary medicine. Resistance determinants to these antimicrobial agents have been described in several staphylococci, yet no inhibition zone-based epidemiological cutoff (ECOFF) values are available to detect populations harboring resistance mechanisms. In this study, we propose disk diffusion inhibition zone ECOFF values of Staphylococcus aureus for apramycin and florfenicol. The susceptibility to apramycin and florfenicol was evaluated by disk diffusion of five S. aureus collections, comprising 352 isolates of animal (n = 265) and human (n = 87) origin. The aggregated distributions of inhibition zone diameters were analyzed by the normalized resistance interpretation method to obtain normalized wild-type (WT) population distributions and corresponding ECOFF values. The putative WT populations of S. aureus were characterized by an inhibition zone ≥15 mm (ECOFF = 15 mm) for apramycin and ≥21 mm for florfenicol (ECOFF = 21 mm). Five nonwild-type (NWT) isolates were detected for apramycin, all without inhibition zone and harboring the apmA gene, whereas five NWT isolates were identified for florfenicol, all carrying the fexA gene. The proposed ECOFF values for apramycin and florfenicol may be a valuable tool in future antimicrobial resistance monitoring and surveillance studies to identify S. aureus NWT populations toward these antimicrobial agents.