9 research outputs found
Association of TLR variants with susceptibility to Plasmodium vivax malaria and parasitemia in the Amazon region of Brazil
BACKGROUND: Plasmodium vivax malaria (Pv-malaria) is still
considered a neglected disease despite an alarming number of
individuals being infected annually. Malaria pathogenesis occurs
with the onset of the vector-parasite-host interaction through
the binding of pathogen-associated molecular patterns (PAMPs)
and receptors of innate immunity, such as toll-like receptors
(TLRs). The triggering of the signaling cascade produces an
elevated inflammatory response. Genetic polymorphisms in TLRs
are involved in susceptibility or resistance to infection, and
the identification of genes involved with Pv-malaria response is
important to elucidate the pathogenesis of the disease and may
contribute to the formulation of control and elimination tools.
METHODOLOGY/PRINCIPAL FINDINGS: A retrospective case-control
study was conducted in an intense transmission area of
Pv-malaria in the state of Amazonas, Brazil. Genetic
polymorphisms (SNPs) in different TLRs, TIRAP, and CD14 were
genotyped by polymerase chain reaction-restriction fragment
length polymorphism (PCR-RFLP) analysis in 325 patients infected
with P. vivax and 274 healthy individuals without malaria
history in the prior 12 months from the same endemic area.
Parasite load was determined by qPCR. Simple and multiple
logistic/linear regressions were performed to investigate
association between the polymorphisms and the occurrence of
Pv-malaria and parasitemia. The C/T (TLR5 R392StopCodon) and T/T
(TLR9 -1486C/T) genotypes appear to be risk factors for
infection by P. vivax (TLR5: C/C vs. C/T [OR: 2.116, 95% CI:
1.054-4.452, p = 0.031]; TLR9: C/C vs. T/T [OR: 1.919, 95% CI:
1.159-3.177, p = 0.010]; respectively). Fever (COEF = 7599.46,
95% CI = 3063.80-12135.12, p = 0.001) and the C/C genotype of
TLR9 -1237C/T (COEF = 17006.63, 95% CI = 3472.83-30540.44, p =
0.014) were independently associated with increased parasitemia
in patients with Pv-malaria. CONCLUSIONS: Variants of TLRs may
predispose individuals to infection by P. vivax. The TLR5
R392StopCodon and TLR9 -1486C/T variants are associated with
susceptibility to Pv-malaria. Furthermore, the TLR9 variant
-1237C/C correlates with high parasitemia
High proportions of asymptomatic and submicroscopic Plasmodium vivax infections in a peri-urban area of low transmission in the Brazilian Amazon
BACKGROUND: Population-based studies conducted in Latin America
have shown a high proportion of asymptomatic and submicroscopic
malarial infections. Considering efforts aiming at regional
elimination, it is important to investigate the role of this
asymptomatic reservoir in malaria transmission in peri-urban
areas. This study aimed to estimate the prevalence of Plasmodium
spp. and gametocyte burden on symptomatic and asymptomatic
infections in the Brazilian Amazon. RESULTS: Two cross-sectional
household surveys (CS) were conducted including all inhabitants
in a peri-urban area of Manaus, western Amazonas State, Brazil.
Malaria parasites were detected by light microscopy (LM) and
qPCR. Sexual stages of Plasmodium spp. were detected by LM and
RT-qPCR. A total of 4083 participants were enrolled during the
two surveys. In CS1, the prevalence of Plasmodium vivax
infections was 4.3% (86/2010) by qPCR and 1.6% (32/2010) by LM.
Fifty percent (43/86) of P. vivax infected individuals (qPCR)
carried P. vivax gametocytes. In CS2, 3.4% (70/2073) of
participants had qPCR-detectable P. vivax infections, of which
42.9% (30/70) of infections were gametocyte positive. The P.
vivax parasite density was associated with gametocyte carriage
(P < 0.001). Sixty-seven percent of P. vivax infected
individuals and 53.4% of P. vivax gametocyte carriers were
asymptomatic. CONCLUSIONS: This study confirms a substantial
proportion of asymptomatic and submicroscopic P. vivax
infections in the study area. Most asymptomatic individuals
carried gametocytes and presented low asexual parasitemia. This
reservoir actively contributes to malaria transmission in the
Brazilian Amazon, underscoring a need to implement more
efficient control and elimination strategies
Association of TLR variants with susceptibility to Plasmodium vivax malaria and parasitemia in the Amazon region of Brazil
BACKGROUND: Plasmodium vivax malaria (Pv-malaria) is still
considered a neglected disease despite an alarming number of
individuals being infected annually. Malaria pathogenesis occurs
with the onset of the vector-parasite-host interaction through
the binding of pathogen-associated molecular patterns (PAMPs)
and receptors of innate immunity, such as toll-like receptors
(TLRs). The triggering of the signaling cascade produces an
elevated inflammatory response. Genetic polymorphisms in TLRs
are involved in susceptibility or resistance to infection, and
the identification of genes involved with Pv-malaria response is
important to elucidate the pathogenesis of the disease and may
contribute to the formulation of control and elimination tools.
METHODOLOGY/PRINCIPAL FINDINGS: A retrospective case-control
study was conducted in an intense transmission area of
Pv-malaria in the state of Amazonas, Brazil. Genetic
polymorphisms (SNPs) in different TLRs, TIRAP, and CD14 were
genotyped by polymerase chain reaction-restriction fragment
length polymorphism (PCR-RFLP) analysis in 325 patients infected
with P. vivax and 274 healthy individuals without malaria
history in the prior 12 months from the same endemic area.
Parasite load was determined by qPCR. Simple and multiple
logistic/linear regressions were performed to investigate
association between the polymorphisms and the occurrence of
Pv-malaria and parasitemia. The C/T (TLR5 R392StopCodon) and T/T
(TLR9 -1486C/T) genotypes appear to be risk factors for
infection by P. vivax (TLR5: C/C vs. C/T [OR: 2.116, 95% CI:
1.054-4.452, p = 0.031]; TLR9: C/C vs. T/T [OR: 1.919, 95% CI:
1.159-3.177, p = 0.010]; respectively). Fever (COEF = 7599.46,
95% CI = 3063.80-12135.12, p = 0.001) and the C/C genotype of
TLR9 -1237C/T (COEF = 17006.63, 95% CI = 3472.83-30540.44, p =
0.014) were independently associated with increased parasitemia
in patients with Pv-malaria. CONCLUSIONS: Variants of TLRs may
predispose individuals to infection by P. vivax. The TLR5
R392StopCodon and TLR9 -1486C/T variants are associated with
susceptibility to Pv-malaria. Furthermore, the TLR9 variant
-1237C/C correlates with high parasitemia
Association of parasitemia with <i>TLR</i> and <i>CD14</i> polymorphisms in <i>Pv</i>-malaria patients.
<p>Association of parasitemia with <i>TLR</i> and <i>CD14</i> polymorphisms in <i>Pv</i>-malaria patients.</p
Genotype and allele frequencies of the TLRs and CD14 polymorphisms in patients with <i>Pv</i>-malaria and healthy controls.
<p>Genotype and allele frequencies of the TLRs and CD14 polymorphisms in patients with <i>Pv</i>-malaria and healthy controls.</p
Study and data analysis flow chart.
<p>We included 599 eligible participants from two cohort studies conducted in Amazonas. Of these, 274 healthy individuals without malaria history in the prior 12 months were included in the “Healthy Group” and 325 patients diagnosed with <i>Pv</i>-malaria infection were included in the “<i>Pv</i>-malaria Cases”. Parasitemia analysis was performed for 208 patients.</p
Clinical and demographic characteristics of the study population.
<p>Clinical and demographic characteristics of the study population.</p
Gasdermin-D activation by SARS-CoV-2 triggers NET and mediate COVID-19 immunopathology
Abstract:
Background:
The release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the molecular mechanisms underlying the release of NETs in COVID-19 remain unclear.
Objectives:
We aim to investigate the role of the Gasdermin-D (GSDMD) pathway on NETs release and the development of organ damage during COVID-19.
Methods:
We performed a single-cell transcriptome analysis in public data of bronchoalveolar lavage. Then, we enrolled 63 hospitalized patients with moderate and severe COVID-19. We analyze in blood and lung tissue samples the expression of GSDMD, presence of NETs, and signaling pathways upstreaming. Furthermore, we analyzed the treatment with disulfiram in a mouse model of SARS-CoV-2 infection.
Results:
We found that the SARS-CoV-2 virus directly activates the pore-forming protein GSDMD that triggers NET production and organ damage in COVID-19. Single-cell transcriptome analysis revealed that the expression of GSDMD and inflammasome-related genes were increased in COVID-19 patients. High expression of active GSDMD associated with NETs structures was found in the lung tissue of COVID-19 patients. Furthermore, we showed that activation of GSDMD in neutrophils requires active caspase1/4 and live SARS-CoV-2, which infects neutrophils. In a mouse model of SARS-CoV-2 infection, the treatment with disulfiram inhibited NETs release and reduced organ damage.
Conclusion:
These results demonstrated that GSDMD-dependent NETosis plays a critical role in COVID-19 immunopathology and suggests GSDMD as a novel potential target for improving the COVID-19 therapeutic strategy