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Fulltext Viral Protein Accumulation of Zika Virus Variants Links with Regulation of Innate Immunity for Differential Control of Viral Replication, Spread, and Response to Interferon

Lu AY, Gustin A, Newhouse D, Gale M

J Virol, 2023 May 31;97(5):e0198222.
PMID: 37162358 DOI: 10.1128/jvi.01982-22

Asian lineage Zika virus (ZIKV) strains emerged globally, causing outbreaks linked with critical clinical disease outcomes unless the virus is effectively restricted by host immunity. We have previously shown that retinoic acid-inducible gene-I (RIG-I) senses ZIKV to trigger innate immunity to direct interferon (IFN) production and antiviral responses that can control ZIKV infection. However, ZIKV proteins have been demonstrated to antagonize IFN. Here, we conducted in vitro analyses to assess how divergent prototypic ZIKV variants differ in virologic properties, innate immune regulation, and infection outcome. We comparatively assessed African lineage ZIKV/Dakar/1984/ArD41519 (ZIKV/Dakar) and Asian lineage ZIKV/Malaysia/1966/P6740 (ZIKV/Malaysia) in a human epithelial cell infection model. De novo viral sequence determination identified amino acid changes within the ZIKV/Dakar genome compared to ZIKV/Malaysia. Viral growth analyses revealed that ZIKV/Malaysia accumulated viral proteins and genome copies earlier and to higher levels than ZIKV/Dakar. Both ZIKV strains activated RIG-I/IFN regulatory factor (IRF3) and NF-κB pathways to induce inflammatory cytokine expression and types I and III IFNs. However, ZIKV/Malaysia, but not ZIKV/Dakar, potently blocked downstream IFN signaling. Remarkably, ZIKV/Dakar protein accumulation and genome replication were rescued in RIG-I knockout (KO) cells late in acute infection, resulting in ZIKV/Dakar-mediated blockade of IFN signaling. We found that RIG-I signaling specifically restricts viral protein accumulation late in acute infection where early accumulation of viral proteins in infected cells confers enhanced ability to limit IFN signaling, promoting viral replication and spread. Our results demonstrate that RIG-I-mediated innate immune signaling imparts restriction of ZIKV protein accumulation, which permits IFN signaling and antiviral actions controlling ZIKV infection. IMPORTANCE ZIKV isolates are classified under African or Asian lineages. Infection with emerging Asian lineage-derived ZIKV strains is associated with increased incidence of neurological symptoms that were not previously reported during infection with African or preemergent Asian lineage viruses. In this study, we utilized in vitro models to compare the virologic properties of and innate immune responses to two prototypic ZIKV strains from distinct lineages: African lineage ZIKV/Dakar and Asian lineage ZIKV/Malaysia. Compared to ZIKV/Dakar, ZIKV/Malaysia accumulates viral proteins earlier, replicates to higher levels, and robustly blocks IFN signaling during acute infection. Early accumulation of ZIKV/Malaysia NS5 protein confers enhanced ability to antagonize IFN signaling, dampening innate immune responses to promote viral spread. Our data identify the kinetics of viral protein accumulation as a major regulator of host innate immunity, influencing host-mediated control of ZIKV replication and spread. Importantly, these findings provide a novel framework for evaluating the virulence of emerging variants.

Matched MeSH terms: Senegal
Genomic Characterization of Yogue, Kasokero, Issyk-Kul, Keterah, Gossas, and Thiafora Viruses: Nairoviruses Naturally Infecting Bats, Shrews, and Ticks

Walker PJ, Widen SG, Firth C, Blasdell KR, Wood TG, Travassos da Rosa AP, et al.

Am J Trop Med Hyg, 2015 Nov;93(5):1041-51.
PMID: 26324724 DOI: 10.4269/ajtmh.15-0344

The genus Nairovirus of arthropod-borne bunyaviruses includes the important emerging human pathogen, Crimean-Congo hemorrhagic fever virus (CCHFV), as well as Nairobi sheep disease virus and many other poorly described viruses isolated from mammals, birds, and ticks. Here, we report genome sequence analysis of six nairoviruses: Thiafora virus (TFAV) that was isolated from a shrew in Senegal; Yogue (YOGV), Kasokero (KKOV), and Gossas (GOSV) viruses isolated from bats in Senegal and Uganda; Issyk-Kul virus (IKV) isolated from bats in Kyrgyzstan; and Keterah virus (KTRV) isolated from ticks infesting a bat in Malaysia. The S, M, and L genome segments of each virus were found to encode proteins corresponding to the nucleoprotein, polyglycoprotein, and polymerase protein of CCHFV. However, as observed in Leopards Hill virus (LPHV) and Erve virus (ERVV), polyglycoproteins encoded in the M segment lack sequences encoding the double-membrane-spanning CCHFV NSm protein. Amino acid sequence identities, complement-fixation tests, and phylogenetic analysis indicated that these viruses cluster into three groups comprising KKOV, YOGV, and LPHV from bats of the suborder Yingochiroptera; KTRV, IKV, and GOSV from bats of the suborder Yangochiroptera; and TFAV and ERVV from shrews (Soricomorpha: Soricidae). This reflects clade-specific host and vector associations that extend across the genus.

Matched MeSH terms: Senegal/epidemiology
Fulltext Cytokine response during non-cerebral and cerebral malaria: evidence of a failure to control inflammation as a cause of death in African adults

Dieye Y, Mbengue B, Dagamajalu S, Fall MM, Loke MF, Nguer CM, et al.

PeerJ, 2016;4:e1965.
PMID: 27168977 DOI: 10.7717/peerj.1965

Background. With 214 million cases and 438,000 deaths in 2015, malaria remains one of the deadliest infectious diseases in tropical countries. Several species of the protozoan Plasmodium cause malaria. However, almost all the fatalities are due to Plasmodium falciparum, a species responsible for the severest cases including cerebral malaria. Immune response to Plasmodium falciparum infection is mediated by the production of pro-inflammatory cytokines, chemokines and growth factors whose actions are crucial for the control of the parasites. Following this response, the induction of anti-inflammatory immune mediators downregulates the inflammation thus preventing its adverse effects such as damages to various organs and death. Methods. We performed a retrospective, nonprobability sampling study using clinical data and sera samples from patients, mainly adults, suffering of non-cerebral or cerebral malaria in Dakar, Sénégal. Healthy individuals residing in the same area were included as controls. We measured the serum levels of 29 biomarkers including growth factors, chemokines, inflammatory and anti-inflammatory cytokines. Results. We found an induction of both pro- and anti-inflammatory immune mediators during malaria. The levels of pro-inflammatory biomarkers were higher in the cerebral malaria than in the non-cerebral malaria patients. In contrast, the concentrations of anti-inflammatory cytokines were comparable in these two groups or lower in CM patients. Additionally, four pro-inflammatory biomarkers were significantly increased in the deceased of cerebral malaria compared to the survivors. Regarding organ damage, kidney failure was significantly associated with death in adults suffering of cerebral malaria. Conclusions. Our results suggest that a poorly controlled inflammatory response determines a bad outcome in African adults suffering of cerebral malaria.

Matched MeSH terms: Senegal
Mutual compensation of the effects of religious and ethnic homogamy on reproduction

Huber S, Fieder M

Am J Hum Biol, 2018 01;30(1).
PMID: 28960565 DOI: 10.1002/ajhb.23064

OBJECTIVES: Homogamy, mating based on similarity, has been demonstrated for a great variety of traits such as age, education, religion, and physical and psychological traits. Recently, pro-fertile effects of religious as well as educational homogamy have been reported. We investigate whether ethnic homogamy also has a pro-fertile effect and whether ethnic and religious homogamy interact in their putative effects on reproduction (in terms of average number of offspring).
METHODS: We analyzed the association between ethnic as well as religious homogamy and woman's average number of offspring based on census data from ten countries provided by IPUMS international, encompassing a total of 1,485,433 married women aged 46-60 years (who have thus completed or almost completed reproduction) and their spouses.
RESULTS: We find a clear pro-fertile but nonadditive effect of both ethnic and religious homogamy, which is most pronounced in the case of double homogamy. Our results further indicate that homogamy for one trait may compensate for heterogamy of the other, albeit countries differ regarding which trait compensates for the other.
CONCLUSIONS: We suggest that the interaction between ethnic homogamy, religious homogamy, and reproduction provides an interesting example for gene-culture co-evolution.

Matched MeSH terms: Senegal
Fulltext Differing courses of genetic evolution of Bradyrhizobium inoculants as revealed by long-term molecular tracing in Acacia mangium plantations

Perrineau MM, Le Roux C, Galiana A, Faye A, Duponnois R, Goh D, et al.

Appl Environ Microbiol, 2014 Sep;80(18):5709-16.
PMID: 25002434 DOI: 10.1128/AEM.02007-14

Introducing nitrogen-fixing bacteria as an inoculum in association with legume crops is a common practice in agriculture. However, the question of the evolution of these introduced microorganisms remains crucial, both in terms of microbial ecology and agronomy. We explored this question by analyzing the genetic and symbiotic evolution of two Bradyrhizobium strains inoculated on Acacia mangium in Malaysia and Senegal 15 and 5 years, respectively, after their introduction. Based on typing of several loci, we showed that these two strains, although closely related and originally sampled in Australia, evolved differently. One strain was recovered in soil with the same five loci as the original isolate, whereas the symbiotic cluster of the other strain was detected with no trace of the three housekeeping genes of the original inoculum. Moreover, the nitrogen fixation efficiency was variable among these isolates (either recombinant or not), with significantly high, low, or similar efficiencies compared to the two original strains and no significant difference between recombinant and nonrecombinant isolates. These data suggested that 15 years after their introduction, nitrogen-fixing bacteria remain in the soil but that closely related inoculant strains may not evolve in the same way, either genetically or symbiotically. In a context of increasing agronomical use of microbial inoculants (for biological control, nitrogen fixation, or plant growth promotion), this result feeds the debate on the consequences associated with such practices.

Matched MeSH terms: Senegal
Analysis of fliC variation among clinical isolates of Burkholderia cepacia

Winstanley C, Hales BA, Morgan JAW, Gallagher MJ, Puthucheary SD, CISSé MF, et al.

J Med Microbiol, 1999 Jul;48(7):657-662.
PMID: 10403416 DOI: 10.1099/00222615-48-7-657

PCR and restriction fragment length polymorphism (RFLP) typing of flagellin genes (fliC) from 57 clinical isolates of Burkholderia cepacia indicated that only type 11 flagellins were present. Twenty-two isolates previously identified as the epidemic UK cystic fibrosis strain were indistinguishable by this method, as were 11 isolates from a pseudo-outbreak in Senegal. Other clinical isolates, including 19 from disparate sources in Malaysia, were separated into nine fliC RFLP groups, exhibiting a large degree of divergence. When isolates were indistinguishable by fliC genotyping, their similarity was confirmed by whole genome macro-restriction analysis with pulsed-field gel electrophoresis following XbaI digestion. The variation in fliC sequences of B. cepacia was far greater than that with B. pseudomallei, supporting the view that 'B. cepacia', as currently defined, may comprise several different genomic species.

Matched MeSH terms: Senegal