Abstract
Although severe COVID-19 in children is rare, they may develop multisystem inflammatory syndrome, long-COVID and downstream effects of COVID-19, including social isolation and disruption of ...education. Data on the effectiveness of the CoronaVac vaccine is scarce during the Omicron period. In Brazil, children between 6 to 11 years are eligible to receive the CoronaVac vaccine. We conducted a test-negative design to estimate vaccine effectiveness using 197,958 tests from January 21, 2022, to April 15, 2022, during the Omicron dominant period in Brazil among children aged 6 to 11 years. The estimated vaccine effectiveness for symptomatic infection was 39.8% (95% CI 33.7–45.4) at ≥14 days post-second dose. For hospital admission vaccine effectiveness was 59.2% (95% CI 11.3–84.5) at ≥14 days. Two doses of CoronaVac in children during the Omicron period showed low levels of protection against symptomatic infection, and modest levels against severe illness.
Trypanosoma cruzi is the etiologic agent of Chagas' disease. Infected cells with T. cruzi activate several responses that promote unbalance of reactive oxygen species (ROS) that may cause DNA damage ...that activate cellular responses including DNA repair processes. In this work, HeLa cells and AC16 human cardiomyocyte cell line were infected with T. cruzi to investigate host cell responses at genome level during parasites intracellular life cycle. In fact, alkaline sensitive sites and oxidized DNA bases were detected in the host cell genetic material particularly in early stages of infection. These DNA lesions were accompanied by phosphorylation of the histone H2Ax, inducing γH2Ax, a marker of genotoxic stress. Moreover, Poly ADP-ribose polymerase-1 (PARP1) and 8-oxoguanine glycosylase (OGG1) are recruited to host cell nuclei, indicating activation of the DNA repair process. In infected cells, chromatin-associated proteins are carbonylated, as a possible consequence of oxidative stress and the nuclear factor erythroid 2-related factor 2 (NRF2) is induced early after infection, suggesting that the host cell antioxidant defenses are activated. However, at late stages of infection, NRF2 is downregulated. Interestingly, host cells treated with glutathione precursor, N-acetyl cysteine, NRF2 activator (Sulforaphane), and also Benznidonazol (BNZ) reduce parasite burst significantly, and DNA damage. These data indicate that the balance of oxidative stress and DNA damage induction in host cells may play a role during the process of infection itself, and interference in these processes may hamper T. cruzi infection, revealing potential target pathways for the therapy support.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To complete its life cycle within the mammalian host,
, the agent of Chagas' disease, must enter cells. Trypomastigotes originating from the insect vector (metacyclic) or from infected cells ...(bloodstream/tissue culture-derived) are the classical infective forms of the parasite and enter mammalian cells in an actin-independent manner. By contrast, amastigotes originating from the premature rupture of infected cells or transformed from swimming trypomastigotes (designated extracellular amastigotes, EAs) require functional intact microfilaments to invade non-phagocytic host cells. Earlier work disclosed the key features of EA-HeLa cell interplay: actin-rich protrusions called 'cups' are formed at EA invasion sites on the host cell membrane that are also enriched in actin-binding proteins, integrins and extracellular matrix elements. In the past decades we described the participation of membrane components and secreted factors from EAs as well as the actin-regulating proteins of host cells involved in what we propose to be a phagocytic-like mechanism of parasite uptake. Thus, regarding this new perspective herein we present previously described EA-induced 'cups' as parasitic synapse since they can play a role beyond its architecture function. In this review, we focus on recent findings that shed light on the intricate interaction between extracellular amastigotes and non-phagocytic HeLa cells.
Enucleated cells or cytoplasts (cells whose nucleus is removed
) represent an unexplored biological model for intracellular infection studies due to the abrupt interruption of nuclear processing and ...new RNA synthesis by the host cell in response to pathogen entry. Using enucleated fibroblasts hosting the protozoan parasite
, we demonstrate that parasite multiplication and biogenesis of large parasitophorous vacuoles in which parasites multiply are independent of the host cell nucleus. Dual RNA sequencing of both host cytoplast and intracellular parasite transcripts identified host transcripts that are more preserved or degraded upon interaction with parasites and also parasite genes that are differentially expressed when hosted by nucleated or enucleated cells. Cytoplasts are suitable host cells, which persist in culture for more than 72 h and display functional enrichment of transcripts related to mitochondrial functions and mRNA translation. Crosstalk between nucleated host
gene expression in response to intracellular parasitism and the parasite gene expression to counteract or benefit from these host responses induces a parasite transcriptional profile favoring parasite multiplication and aerobic respiration, and a host-parasite transcriptional landscape enriched in host cell metabolic functions related to NAD, fatty acid, and glycolytic metabolism. Conversely, interruption of host nucleus-parasite cross talk by infection of enucleated cells generates a host-parasite transcriptional landscape in which cytoplast transcripts are enriched in phagolysosome-related pathway, prosurvival, and SerpinB-mediated immunomodulation. In addition, predictive
analyses indicated that parasite transcript products secreted within cytoplasts interact with host transcript products conserving the host V-ATPase proton translocation function and glutamine/proline metabolism. The collective evidence indicates parasite-mediated control of host cell transcripts half-life that is beneficial to parasite intracellular multiplication and escape from host immune responses. These findings will contribute to improved drug targeting and serve as database for
-host cell interactions.
Pathological processes such as bacterial, viral and parasitic infections can generate a plethora of responses such as, but not restricted to, oxidative stress that can be harmful to the host and the ...pathogen. This stress occurs when there is an imbalance between reactive oxygen species produced and antioxidant factors produced in response to the infection. This imbalance can lead to DNA lesions in both infected cells as well as in the pathogen. The effects of the host response on the parasite lead to several kinds of DNA damage, causing alterations in the parasite's metabolism; the reaction and sensitivity of the parasite to these responses are related to the DNA metabolism and life cycle of each parasite. The present review will discuss the survival strategies developed by host cells and Trypanosoma cruzi, focusing on the DNA repair mechanisms of these organisms throughout infection including the relationship between DNA damage, stress response features, and the unique characteristics of these diseases.
Infection with SARS-CoV-2 during pregnancy increases the risk of severe negative maternal and foetal clinical outcomes.1 In the general population, the SARS-CoV-2 B.1.1.529 (omicron) variant can ...evade both natural and vaccine-induced protection,2 highlighting the importance of booster doses.3 However, little is known about the vaccine effectiveness of a booster dose against COVID-19 in pregnant people, and no data have been published for those with a primary series of CoronaVac (inactivated-virus vaccine).4,5 In this study, we investigated the vaccine effectiveness in pregnant people who received two doses of CoronaVac to estimate the additional protection provided by a booster dose with BNT162b2 (mRNA vaccine) during the omicron period. The primary assumption of the test-negative design is that people seeking and getting tested would be influenced by similar pressures, regardless of their vaccination status,8 and a limitation is the absence of information of pregnancy status at the time of vaccination and the precise gestational age at the time of testing. Supplementary Material Supplementary appendix Tested positive (n=6280) Severe cases* (n=434) Tested negative (n=4506) Vaccine effectiveness for symptomatic infection (95% CI) Vaccine effectiveness for severe cases (95% CI) Two doses of CoronaVac only ≥14 days 5036 (80·2%) 381 (87·8%) 3156 (70·0%) Reference Reference BNT162b2 booster dose 0–13 days 194 (3·1%) 16 (3·7%) 188 (4·2%) 46·4% (33·2–57·0%) 43·2% (1·7–67·2%) ≥14 days 1050 (16·7%) 37 (8·5%) 1162 (25·8%) 37·7% (28·9–45·3%) 68·4% (52·6–78·9%) Table Adjusted vaccine effectiveness against symptomatic infection and severe cases for pregnant people receiving a BNT162b2 booster dose (two doses of CoronaVac plus BNT162b2) at days 0–13 and 14 days or more
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
is the etiologic agent of Chagas' disease. It is known that amastigotes derived from trypomastigotes in the extracellular milieu are infective
and
. Extracellular amastigotes (EAs) have a ...stage-specific surface antigen called Ssp-4, a GPI-anchored glycoprotein that is secreted by the parasites. By immunoprecipitation with the Ssp-4-specific monoclonal antibodies (mAb) 2C2 and 1D9, we isolated the glycoprotein from EAs. By mass spectrometry, we identified the core protein of Ssp-4 and evaluated mRNA expression and the presence of Ssp-4 carbohydrate epitopes recognized by mAb1D9. We demonstrated that the carbohydrate epitope recognized by mAb1D9 could promote host cell invasion by EAs. Although infectious EAs express lower amounts of Ssp-4 compared with less-infectious EAs (at the mRNA and protein levels), it is the glycosylation of Ssp-4 (identified by mAb1D9 staining only in infectious strains and recognized by galectin-3 on host cells) that is the determinant of EA invasion of host cells. Furthermore, Ssp-4 is secreted by EAs, either free or associated with parasite vesicles, and can participate in host-cell interactions. The results presented here describe the possible role of a carbohydrate moiety of
surface glycoproteins in host cell invasion by EA forms, highlighting the potential of these moieties as therapeutic and vaccine targets for the treatment of Chagas' disease.
Little is known about vaccine effectiveness over time among adolescents, especially against the SARS-CoV-2 omicron (B.1.1.529) variant. This study assessed the associations between time since ...two-dose vaccination with BNT162b2 and the occurrence of symptomatic SARS-CoV-2 infection and severe COVID-19 among adolescents in Brazil and Scotland.
We did test-negative, case-control studies in adolescents aged 12–17 years with COVID-19-related symptoms in Brazil and Scotland. We linked records of SARS-CoV-2 RT-PCR and antigen tests to national vaccination and clinical records. We excluded tests from individuals who did not have symptoms, were vaccinated before the start of the national vaccination programme, received vaccines other than BNT162b2 or a SARS-CoV-2 booster dose of any kind, or had an interval between their first and second dose of fewer than 21 days. Additionally, we excluded negative SARS-CoV-2 tests recorded within 14 days of a previous negative test, negative tests recorded within 7 days after a positive test, any test done within 90 days after a positive test, and tests with missing sex and location information. Cases (SARS-CoV-2 test-positive adolescents) and controls (test-negative adolescents) were drawn from a sample of individuals in whom tests were collected within 10 days of symptom onset. We estimated the adjusted odds ratio and vaccine effectiveness against symptomatic COVID-19 for both countries and against severe COVID-19 (hospitalisation or death) for Brazil across fortnightly periods.
We analysed 503 776 tests from 2 948 538 adolescents in Brazil between Sept 2, 2021, and April 19, 2022, and 127 168 tests from 404 673 adolescents in Scotland between Aug 6, 2021, and April 19, 2022. Vaccine effectiveness peaked at 14–27 days after the second dose in both countries during both waves, and was significantly lower against symptomatic infection during the omicron-dominant period in Brazil (64·7% 95% CI 63·0–66·3) and in Scotland (82·6% 80·6–84·5), than it was in the delta-dominant period (80·7% 95% CI 77·8–83·3 in Brazil and 92·8% 85·7–96·4 in Scotland). Vaccine efficacy started to decline from 27 days after the second dose for both countries, reducing to 5·9% (95% CI 2·2–9·4) in Brazil and 50·6% (42·7–57·4) in Scotland at 98 days or more during the omicron-dominant period. In Brazil, protection against severe disease remained above 80% from 28 days after the second dose and was 82·7% (95% CI 68·8–90·4) at 98 days or more after receiving the second dose.
We found waning vaccine protection of BNT162b2 against symptomatic COVID-19 infection among adolescents in Brazil and Scotland from 27 days after the second dose. However, protection against severe COVID-19 outcomes remained high at 98 days or more after the second dose in the omicron-dominant period. Booster doses for adolescents need to be considered.
UK Research and Innovation (Medical Research Council), Scottish Government, Health Data Research UK BREATHE Hub, Fiocruz, Fazer o Bem Faz Bem programme, Brazilian National Research Council, and Wellcome Trust.
For the Portuguese translation of the abstract see Supplementary Materials section.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A new microplate assay for Ca(2+)-induced platelet aggregation as detected by Giemsa dye was used to screen marine invertebrate samples from the Philippines for inhibitors of human platelet ...aggregation. Out of 261 crude methanol extracts of marine sponges and tunicates, 25 inhibited aggregation at 2 mg/ml. Inhibition of agonist-induced aggregation in an aggregometer was used to confirm results of the microplate assay and to determine the specific mode of inhibition of 2 samples. The marine sponge Xestospongia sp. yielded a xestospongin/araguspongine-type molecule that inhibited collagen-induced aggregation by 87% at 2 micro g/ml, and epinephrine-induced aggregation by 78% at 20 micro g/ml, while the marine sponge Aplysina sp. yielded 5,6-dibromotryptamine, which inhibited epinephrine-induced aggregation by 51% at 20 micro g/ml. In this study we have found that the microplate assay is a simple, inexpensive, yet useful preliminary tool to qualitatively screen a large number of marine samples for antiplatelet aggregation activity.
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