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Research Project
Center for Interdisciplinary Research in Health
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Publications
ESAT-6 a Major Virulence Factor of Mycobacterium tuberculosis
Publication . Anes, Elsa; Pires, David; Mandal, Manoj; Azevedo-Pereira, José Miguel
Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), is one of the most successfully adapted human pathogens. Human-to-human transmission occurs at high rates through aerosols containing bacteria, but the pathogen evolved prior to the establishment of crowded populations. Mtb has developed a particular strategy to ensure persistence in the host until an opportunity for transmission arises. It has refined its lifestyle to obviate the need for virulence factors such as capsules, flagella, pili, or toxins to circumvent mucosal barriers. Instead, the pathogen uses host macrophages, where it establishes intracellular niches for its migration into the lung parenchyma and other tissues and for the induction of long-lived latency in granulomas. Finally, at the end of the infection cycle, Mtb induces necrotic cell death in macrophages to escape to the extracellular milieu and instructs a strong inflammatory response that is required for the progression from latency to disease and transmission. Common to all these events is ESAT-6, one of the major virulence factors secreted by the pathogen. This narrative review highlights the recent advances in understanding the role of ESAT-6 in hijacking macrophage function to establish successful infection and transmission and its use as a target for the development of diagnostic tools and vaccines.
Modulation of Cystatin F in Human Macrophages Impacts Cathepsin-Driven Killing of Multidrug-Resistant Mycobacterium tuberculosis
Publication . Mandal, Manoj; Pires, David; Catalão, Maria João; Azevedo-Pereira, José Miguel; Anes, Elsa
Tuberculosis (TB) treatment relies primarily on 70-year-old drugs, and prophylaxis suffers from the lack of an effective vaccine. Among the 10 million people exhibiting disease symptoms yearly, 450,000 have multidrug or extensively drug-resistant (MDR or XDR) TB. A greater understanding of host and pathogen interactions will lead to new therapeutic interventions for TB eradication. One of the strategies will be to target the host for better immune bactericidal responses against the TB causative agent Mycobacterium tuberculosis (Mtb). Cathepsins are promising targets due to their manipulation of Mtb with consequences such as decreased proteolytic activity and improved pathogen survival in macrophages. We recently demonstrated that we could overcome this enzymatic blockade by manipulating protease inhibitors such as cystatins. Here, we investigate the role of cystatin F, an inhibitor that we showed previously to be strongly upregulated during Mtb infection. Our results indicate that the silencing of cystatin F using siRNA increase the proteolytic activity of cathepsins S, L, and B, significantly impacting pathogen intracellular killing in macrophages. Taken together, these indicate the targeting of cystatin F as a potential adjuvant therapy for TB, including MDR and XDR-TB.
The resilience scale in portuguese adults under assisted reproductive techniques
Publication . Romeiro, Joana; Nogueira, Paulo Jorge; Hall, Jenny; Caldeira, Sílvia
Assessing resilience response to an adverse event such as infertility requires measuring the same construct adequately and accurately by nurses. The objective of this study was to explore the validity and reliability of the Portuguese version of the Resilience Scale for adults. A cross-sectional and methodological design was used, and factor analyses were performed. The sample comprised 140 adult Portuguese individuals under fertility treatment recruited from health-related websites. The findings yielded a bad fit of the hypothesized Resilience Scale structure with the observed data. Instead, a 21-item tool with a four-factor structure revealed high internal consistency (0.94). The tool correlated positively and significantly to the Portuguese version of the Spiritual Well-Being Questionnaire and was negatively associated and lacked correlation with the Fertility Adjustment Scale. The 21-item Resilience Scale is a reliable tool suitable to measure resilience in Portuguese adults under assisted reproductive techniques. This tool offers the opportunity of early recognition by health professionals aiming to enhance patients' coping skills effectively and promote positive psychological and mental health outcomes.
Development of Chitosan Particles Loaded with siRNA for Cystatin C to Control Intracellular Drug-Resistant Mycobacterium tuberculosis
Publication . Pires, David; Mandal, Manoj; Matos, Ana I.; Peres, Carina; Catalão, Maria João; Azevedo-Pereira, José M.; Satchi-Fainaro, Ronit; Florindo, Helena F; Anes, Elsa
The golden age of antibiotics for tuberculosis (TB) is marked by its success in the 1950s of the last century. However, TB is not under control, and the rise in antibiotic resistance worldwide is a major threat to global health care. Understanding the complex interactions between TB bacilli and their host can inform the rational design of better TB therapeutics, including vaccines, new antibiotics, and host-directed therapies. We recently demonstrated that the modulation of cystatin C in human macrophages via RNA silencing improved the anti-mycobacterial immune responses to Mycobacterium tuberculosis infection. Available in vitro transfection methods are not suitable for the clinical translation of host-cell RNA silencing. To overcome this limitation, we developed different RNA delivery systems (DSs) that target human macrophages. Human peripheral blood-derived macrophages and THP1 cells are difficult to transfect using available methods. In this work, a new potential nanomedicine based on chitosan (CS-DS) was efficiently developed to carry a siRNA-targeting cystatin C to the infected macrophage models. Consequently, an effective impact on the intracellular survival/replication of TB bacilli, including drug-resistant clinical strains, was observed. Altogether, these results suggest the potential use of CS-DS in adjunctive therapy for TB in combination or not with antibiotics.
Validation of the Portuguese version of the Fertility Adjustment Scale
Publication . Romeiro, Joana; Nogueira, Paulo Jorge; Caldeira, Sílvia
There is an urgent need to provide healthcare professionals and midwives with validated tools as to improve fertility adjustment and promote well-being of couples with infertility. The purpose of this study was to test validity of the Fertility Adjustment Scale among people undergoing assisted reproductive techniques. A cross-sectional and methodological study was conducted, and a total of 104 Portuguese adults undergoing fertility treatment were recruited through fertility-related websites. The Fertility Adjustment Scale was administered along with the Spiritual Well-Being Questionnaire and the Resilience Scale for adults as a measure of concurrent validity. Scores revealed the sample's lack of adjustment to fertility. A significant correlation with measures of resilience provided evidence of convergent validity. There was a significant association of fertility adjustment with time of consultation and the cause of infertility. A Fertility Adjustment Scale with six items is a reliable tool that offers early recognition of patients' difficulties in adaptation to fertility problems during assisted reproductive techniques, which could be beneficial in not only an early recognition of healthcare intervention but of a more individualized approach to such patients.
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Funding agency
Fundação para a Ciência e a Tecnologia
Funding programme
6817 - DCRRNI ID
Funding Award Number
UIDB/04279/2020