Biology subjects

Mendonca, S.

Publications and source records attributed to Mendonca, S..

6 recordsLinked to original sources

bioRxiv2023

High capacity of Brazilian Aedes aegypti populations to transmit a locally circulating lineage of Chikungunya virus

The global incidence of chikungunya has surged in recent decades, with South America, particularly Brazil, experiencing devastating outbreaks. The primary vector for transmitting CHIKV in urban areas is the mosquito species Aedes aegypti, which is very abundant in Brazil. However, little is known about the impact of locally circulating CHIKV genotypes and specific combinations of mosquito populations on vector competence. In this study, we analyzed and compared the infectivity and transmissibility of a recently isolated CHIKV-ECSA lineage from Brazil among four Ae. aegypti populations collected from different regions of the country. When exposed to CHIKV-infected mice for blood feeding, all mosquito populations showed high infection rates and dissemination efficiency. Moreover, using a mouse model to assess transmission rates in a manner that better mirrors natural cycles, we observed that these populations exhibit highly efficient transmission rates of CHIKV-ECSA. Our findings underscore the robust capability of Brazilian Ae. aegypti populations to transmit the locally circulating CHIKV-ECSA lineage, potentially explaining its higher prevalence compared to the Asian lineage also introduced in Brazil. Author SummaryChikungunya virus (CHIKV) is an alphavirus transmitted by mosquitoes, gaining attention due to its rapid global spread and public health impact. Initially isolated in Tanzania in 1952, it was confined to Africa, Asia, and the Indian subcontinent. Local transmission of CHIKV in the Americas began in December 2013, leading to a 2014 epidemic. The Aedes aegypti mosquito, prevalent in Brazil, is suspected as the primary vector. Yet, our understanding of how different mosquito populations and virus lineages impact spread is limited. In this Brazilian study, we collected mosquitoes from four regions, exposing them to the local African ECSA lineage of CHIKV. Remarkably, all mosquito populations exhibited high infection rates and efficient virus transmission to vertebrate hosts. This research sheds light on why the ECSA chikungunya lineage is spreading rapidly in Brazil. The Brazilian Ae. aegypti mosquitoes appear to possess exceptional capabilities in transmitting African ECSA lineage of CHIKV, potentially contributing to its rapid dissemination within the country and neighboring regions. Comprehending these dynamics is vital for developing strategies to control and mitigate the impact of chikungunya in affected areas.

immunology↗

bioRxiv2022

Modulation of fibroblasts phenotype by colorectal cancer cells-secreted factors is mostly independent of oncogenic KRAS

KRAS mutations have been shown to extend their oncogenic effects beyond the cancer cell, influencing the tumor microenvironment components. Herein, we studied the impact of mutant KRAS on the modulation of cancer-associated fibroblasts (CAFs) pro-tumorigenic properties. To do so, we challenged CCD-18Co normal-like colon fibroblasts with control media (DMEM alone and DMEM+rhTGF{beta}1 media), and conditioned media from control and KRAS silenced colorectal cancer (CRC) cells. Two mutant KRAS CRC cell lines-HCT116 and LS174T, were used. Major pro-tumorigenic fibroblasts phenotypic features, such as -SMA expression, TGF{beta}1 and HGF production, extracellular matrix components and metalloproteinases expression, collagen contraction and migration capacities, were analyzed upon fibroblast challenging with cells conditioned media. Our results showed that the mutant KRAS CRC cells-secreted factors are capable of turning normal-like fibroblasts into CAF-like by modulating -SMA expression, TGF{beta}1 and HGF production and migration capacity, though in a cell line-specific manner. In this scenario, oncogenic KRAS showed to play a secondary role, regulating only discrete features in each cancer cell-educated fibroblasts. For instance, in HCT116, KRAS impairs fibroblasts migration and in LS174T it promotes -SMA expression. In summary, our work suggests that mutant KRAS does not play a major role in controlling the CRC cell secreted factors that modulate fibroblasts behavior. This KRAS-independent modulation of fibroblast pro-tumorigenic features is likely to negatively impact the response to KRAS inhibitors, thus standing as a putative mechanism of resistance to KRAS-inhibition, with possible therapeutical relevance.

cancer biology↗

bioRxiv2021

Mutant KRAS modulates colorectal cancer cells invasive response to fibroblast-secreted factors through the HGF/C-MET axis

Genetic alterations influence the malignant potential of cancer cells, and so does the tumor microenvironment. Herein, we combined the study of KRAS oncogenic effects in colorectal cancer cells with the influence of fibroblasts-derived factors. Results revealed that mutant KRAS regulates cell fate through both autonomous and non-autonomous signaling mechanisms. Specifically, processes such as proliferation and cell-cell aggregation were autonomously controlled by mutant KRAS independently of the stimulation with fibroblasts conditioned media. However, cancer cell invasion revealed to be a KRAS-dependent non-autonomous effect, resulting from the cooperation between fibroblasts-derived HGF and mutant KRAS regulation of C-MET expression. C-MET downregulation upon KRAS silencing rendered cells less responsive to HGF and thus less invasive. Yet, in one cell line, KRAS inhibition triggered invasion upon stimulation with fibroblasts conditioned media. Inhibition of PIK3CA oncogene did not promoted invasion, thus showing a KRAS-specific effect. Moreover, the invasive capacity also depended on the HGF-C-MET axis. Overall, our study awards oncogenic KRAS an important role in modulating the response to fibroblast-secreted factors either by promoting or impairing invasion, and depicts the HGF-C-MET axis as a putative therapeutic target to impair the invasive properties of mutant KRAS cancer cells. SignificanceTargeting mutant KRAS cancers is an urgent clinical need. HGF-C-MET axis inhibition arises as a possible strategy to target mutant KRAS CRC, both primary and metastatic tumors. Additional informationO_ST_ABSFinancial supportC_ST_ABSThis work was supported through FEDER funds through the Operational Programme for Competitiveness Factors (COMPETE 2020), Programa Operacional de Competitividade e Internacionalizacao (POCI), Programa Operacional Regional do Norte (Norte 2020), European Regional Development Fund (ERDF), and by National Funds through the Portuguese Foundation for Science and Technology (FCT) (PTDC/MED-ONC/31354/2017). PDC is a PhD student from Doctoral Program in Pathology and Molecular Genetics from the Institute of Biomedical Sciences Abel Salazar (ICBAS, University of Porto) and she is funded through a PhD fellowship (SFRH/BD/131156/2017) awarded by the FCT. FM is a PhD student from Doctoral Program in Biomedicine from the Faculty of Medicine of the University of Porto and she is funded through a PhD fellowship (SFRH/BD/143669/2019) awarded by the FCT. SM is a PhD student from Doctoral Program in Biomedicine from the Faculty of Medicine of the University of Porto and she is funded through a PhD fellowship (SFRH/BD/143642/2019) awarded by the FCT. AR is a junior researcher hired by IPATIMUP under the CaTCh project funded by FEDER and FCT (POCI-01-0145-FEDER-031354). ALM is a PhD student from Doctoral Program in Biomedicine from the Faculty of Medicine of the University of Porto and she is funded through a PhD fellowship (2020.08932.BD) awarded by the FCT. MJO is principal researcher at INEB. SV is hired by IPATIMUP under norma transitoria do DL n.{o} 57/2016 alterada pela lei n.{o} 57/2017.

cancer biology↗

bioRxiv2020

Putative Pseudolysogeny-Dependent Phage Gene Implicated in the Superinfection Resistance of Cutibacterium acnes

BackgroundBacteriophage therapy is a promising option to minimize the risk of treatment-associated antibiotic resistance in Cutibacterium acnes. A novel phage (Aquarius) was isolated and analyzed to explore characteristics of C. acnes phages that may confer lysis-evasion properties. Materials and MethodsPhage superinfection resistance assays were performed with a range of C. acnes phages, which were assayed for pseudolysogeny via phage release assays and episome PCR. Bioinformatics and qRT-PCR were used to identify candidate genes related to observed phenotypes. ResultsAssay findings indicated that infected C. acnes strains were broadly resistant to superinfection and were capable of forming stable pseudolysogens. A conserved Ltp family-like gene contained protein signatures which may be contributing to phage-mediated superinfection resistance in a pseudolysogeny-dependent manner. ConclusionsC. acnes bacteria are capable of harboring phage pseudolysogens, and this phenomenon may result in superinfection resistance, necessitating consideration in targeting optimization of C. acnes phage-based therapy.

microbiology↗

bioRxiv2020

IFT88 transports Gucy2d, a guanylyl cyclase, to maintain sensory cilia function in Drosophila

Cilia are involved in a plethora of motility and sensory-related functions. Ciliary defects cause several ciliopathies, some of which with late-onset, suggesting cilia are actively maintained. While much is known about cilia assembly, little is understood about the mechanisms of their maintenance. Given that intraflagellar transport (IFT) is essential for cilium assembly, we investigated the role of one of its main players, IFT88, in ciliary maintenance. We show that DmIFT88, the Drosophila melanogaster orthologue of IFT88, continues to move along fully formed sensory cilia, and that its acute knockdown in the ciliated neurons of the adult affects sensory behaviour. We further identify DmGucy2d, the Drosophila guanylyl cyclase 2d, as a DmIFT88 cargo, whose loss also leads to defects in sensory behaviour maintenance. DmIFT88 binds to the intracellular part of DmGucy2d, which is evolutionarily conserved and mutated in several degenerative retina diseases, taking the cyclase into the cilia. Our results offer a novel mechanism for the maintenance of sensory cilia function and its potential role in human diseases.

cell biology↗

bioRxiv2019

Herpes Simplex Virus Infection, Acyclovir and IVIG Treatment All Independently Cause Gut Dysbiosis.

Herpes simplex virus 1 (HSV) is a ubiquitous human virus resident in a majority of the global population as a latent infection. Acyclovir (ACV), is the standard of care drug used to treat primary and recurrent infections, supplemented in some patients with intravenous immunoglobulin (IVIG) treatment to suppress deleterious inflammatory responses. We found that HSV, ACV and IVIG can all independently disrupt the gut bacterial community in a sex biased manner when given to uninfected mice. Treatment of HSV infected mice with ACV or IVIG alone or together revealed complex interactions between these drugs and infection that caused pronounced sex biased dysbiosis. ACV reduced Bacteroidetes levels in male but not female mice, while levels of the Anti-inflammatory Clostridia (AIC) were reduced in female but not male mice, which is significant as these taxa are associated with protection against the development of GVHD in hematopoietic stem cell transplant (HSCT) patients. Gut barrier dysfunction is associated with GVHD in HSCT patients and ACV also decreased Akkermansia muciniphila, which is important for maintaining gut barrier functionality. Cumulatively, our data suggest that long-term prophylactic ACV treatment of HSCT patients may contribute to GVHD and potentially impact immune reconstitution. These data have important implications for other clinical settings, including HSV eye disease and genital infections, where ACV is given long-term. Author SummaryPrimary and reactivated HSV and VZV infections are treated with Acyclovir (ACV), an antiviral drug that blocks viral DNA synthesis. In some patients IVIG is used as adjunctive therapy to block deleterious inflammation. Long term preventative treatment of patients who receive stem transplants for various blood cancers has been successful in preventing life threatening reactivated HSV and VZV infections, but GVHD remains a major factor limiting transplant success. Studies reported here reveal that HSV infection, ACV and IVIG given alone can all disrupt the gut microbiota and that complex interactions between these drugs and infection results in even more pronounced sex biased changes in the gut bacteria community structure. Importantly, ACV treatment decreased the levels of specific bacterial taxa, including the anti-inflammatory Clostriodia and Bacteroidetes that have been shown to protect against development of GVHD in stem cell transplant patients. These data suggest that long term preventative treatment of patients with ACV may contribute to GVHD in transplant patients and have negative consequences in other HSV induced diseases treated long term with ACV. The health effects of long term ACV and IVIG treatments warrant further clinical studies.

microbiology↗