Over the past decade, the scientific committee has called for broadening our horizons in understanding host-microbe interactions and infectious disease progression. Owing to the fact that the human gut harbors trillions of microbes that exhibit various roles including the production of vitamins, absorption of nutrients, pathogen displacement, and development of the host immune system, particular attention has been given to the use of germ-free (GF) animal models in unraveling the effect of the gut microbiota on the physiology and pathophysiology of the host. In this review, we discuss common methods used to generate GF fruit fly, zebrafish, and mice model systems and highlight the use of these GF model organisms in addressing the role of gut-microbiota in gut-related disorders (metabolic diseases, inflammatory bowel disease, and cancer), and in activating host defense mechanisms and amending pathogenic virulence.

https://www.mdpi.com/2073-4409/9/11/2401/pdf

The Microbiota and Gut-Related Disorders: Insights from Animal Models

Obesity, one of the most common chronic health conditions worldwide, is a multifactorial disease caused by complex genetic and environmental interactions. Several association studies have revealed a considerable number of candidate loci for obesity; however, the genotype–phenotype correlations remain unclear. To date, no comprehensive systematic review has been conducted to investigate the genetic risk factors for obesity among Arabs. This study aimed to systematically review the genetic polymorphisms that are significantly associated with obesity in Arabs. We searched four literature databases (PubMed, Science Direct, Scopus, and Google Scholar) from inception until May 2020 to obtain all reported genetic data related to obesity in Arab populations. Quality assessment and data extraction were performed individually by three investigators. In total, 59 studies comprising a total of 15,488 cases and 9,760 controls were included in the systematic review. A total of 76 variants located within or near 49 genes were reported to be significantly associated with obesity. Among the 76 variants, two were described as unique to Arabs, as they have not been previously reported in other populations, and 19 were reported to be distinctively associated with obesity in Arabs but not in non-Arab populations. There appears to be a unique genetic and clinical susceptibility profile of obesity in Arab patients.

/pdf/genetic-polymorphisms-associated-with-obesity-in-the-arab-1fkhb8o0e8.pdf

Genetic polymorphisms associated with obesity in the Arab world: a systematic review

The ubiquitin pathway is highly conserved across the eukaryotic domain of life and plays an essential role in a plethora of cellular processes. It is not surprising that many intracellular bacterial pathogens often target the essential host ubiquitin pathway. The intracellular bacterial pathogen Legionella pneumophila injects into the host cell cytosol multiple classes of classical and novel ubiquitin-modifying enzymes that modulate diverse ubiquitin-related processes in the host cell. Most of these pathogen-injected proteins, designated as effectors, mimic known E3-ubiquitin ligases through harboring F-box or U-box domains. The classical F-box effector, AnkB targets host proteins for K48-linked polyubiquitination, which leads to excessive proteasomal degradation that is required to generate adequate supplies of amino acids for metabolism of the pathogen. In contrast, the SidC and SdcA effectors share no structural similarity to known eukaryotic ligases despite having E3-ubiquitin ligase activity, suggesting that the number of E3-ligases in eukaryotes is under-represented. L. pneumophila also injects into the host many novel ubiquitin-modifying enzymes, which are the SidE family of effectors that catalyze phosphoribosyl-ubiquitination of serine residue of target proteins, independently of the canonical E1-2-3 enzymatic cascade. Interestingly, the environmental bacterium, L. pneumophila, has evolved within a diverse range of amoebal species, which serve as the natural hosts, while accidental transmission through contaminated aerosols can cause pneumonia in humans. Therefore, it is likely that the novel ubiquitin-modifying enzymes of L. pneumophila were acquired by the pathogen through interkingdom gene transfer from the diverse natural amoebal hosts. Furthermore, conservation of the ubiquitin pathway across eukaryotes has enabled these novel ubiquitin-modifying enzymes to function similarly in mammalian cells. Studies on the biological functions of these effectors are likely to reveal further novel ubiquitin biology and shed further lights on the evolution of ubiquitin.

https://www.mdpi.com/2218-273X/11/1/112/pdf

Evolution and Adaptation of Legionella pneumophila to Manipulate the Ubiquitination Machinery of Its Amoebae and Mammalian Hosts

The innate immune response provides the first line of defense against invading pathogens, and immune disorders cause a variety of diseases. The fruit fly Drosophila melanogaster employs multiple innate immune reactions to resist infection. First, epithelial tissues function as physical barriers to prevent pathogen invasion. In addition, macrophage-like plasmatocytes eliminate intruders through phagocytosis, and lamellocytes encapsulate large particles, such as wasp eggs, that cannot be phagocytosed. Regarding humoral immune responses, the fat body, equivalent to the mammalian liver, secretes antimicrobial peptides into hemolymph, killing bacteria and fungi. Drosophila has been shown to be a powerful in vivo model for studying the mechanism of innate immunity and host-pathogen interactions because Drosophila and higher organisms share conserved signaling pathways and factors. Moreover, the ease with which Drosophila genetic and physiological characteristics can be manipulated prevents interference by adaptive immunity. In this review, we discuss the signaling pathways activated in Drosophila innate immunity, namely, the Toll, Imd, JNK, JAK/STAT pathways, and other factors, as well as relevant regulatory networks. We also review the mechanisms by which different tissues, including hemocytes, the fat body, the lymph gland, muscles, the gut and the brain coordinate innate immune responses. Furthermore, the latest studies in this field are outlined in this review. In summary, understanding the mechanism underlying innate immunity orchestration in Drosophila will help us better study human innate immunity-related diseases.

/pdf/drosophila-innate-immunity-involves-multiple-signaling-3o8l5erk.pdf

Drosophila Innate Immunity Involves Multiple Signaling Pathways and Coordinated Communication Between Different Tissues

Diversion of the Legionella pneumophila-containing vacuole (LCV) from the host endosomal-lysosomal degradation pathway is one of the main virulence features essential for manifestation of Legionnaires’ pneumonia. Many of the ∼350 Dot/Icm-injected effectors identified in L. pneumophila have been shown to interfere with various host pathways and processes, but no L. pneumophila effector has ever been identified to be indispensable for lysosomal evasion. While most single effector mutants of L. pneumophila do not exhibit a defective phenotype within macrophages, we show that the MavE effector is essential for intracellular growth of L. pneumophila in human monocyte-derived macrophages (hMDMs) and amoebae and for intrapulmonary proliferation in mice. The mavE null mutant fails to remodel the LCV with endoplasmic reticulum (ER)-derived vesicles and is trafficked to the lysosomes where it is degraded, similar to formalin-killed bacteria. During infection of hMDMs, the MavE effector localizes to the poles of the LCV membrane. The crystal structure of MavE, resolved to 1.8 A, reveals a C-terminal transmembrane helix, three copies of tyrosine-based sorting motifs, and an NPxY eukaryotic motif, which binds phosphotyrosine-binding domains present on signaling and adaptor eukaryotic proteins. Two point mutations within the NPxY motif result in attenuation of L. pneumophila in both hMDMs and amoeba. The substitution defects of P78 and D64 are associated with failure of vacuoles harboring the mutant to be remodeled by the ER and results in fusion of the vacuole to the lysosomes leading to bacterial degradation. Therefore, the MavE effector of L. pneumophila is indispensable for phagosome biogenesis and lysosomal evasion. IMPORTANCE Intracellular proliferation of Legionella pneumophila within a vacuole in human alveolar macrophages is essential for manifestation of Legionnaires’ pneumonia. Intravacuolar growth of the pathogen is totally dependent on remodeling the L. pneumophila-containing vacuole (LCV) by the ER and on its evasion of the endosomal-lysosomal degradation pathway. The pathogen has evolved to inject ∼350 protein effectors into the host cell where they modulate various host processes, but no L. pneumophila effector has ever been identified to be indispensable for lysosomal evasion. We show that the MavE effector localizes to the poles of the LCV membrane and is essential for lysosomal evasion and intracellular growth of L. pneumophila and for intrapulmonary proliferation in mice. The crystal structure of MavE shows an NPxY eukaryotic motif essential for ER-mediated remodeling and lysosomal evasion by the LCV. Therefore, the MavE effector of L. pneumophila is indispensable for phagosome biogenesis and lysosomal evasion.

https://mbio.asm.org/content/mbio/12/1/e03458-20.full.pdf

An Indispensable Role for the MavE Effector of Legionella pneumophila in Lysosomal Evasion.

Owing to the genetic similarities and conserved pathways between a fruit fly and mammals, the use of the Drosophila model as a platform to unveil novel mechanisms of infection and disease progression has been justified and widely instigated Gaining proper insight into host-pathogen interactions and identifying chief factors involved in host defense and pathogen virulence in Drosophila serves as a foundation to establish novel strategies for infectious disease prevention and control in higher organisms, including humans

/pdf/drosophila-as-a-model-organism-in-host-pathogen-interaction-19ywrsx000.pdf

Drosophila as a Model Organism in Host-Pathogen Interaction Studies.

Objectives To investigate the mutational spectrum in the HBB gene in Arab patients with β-thal. Methods Authors searched five databases (PubMed, Science Direct, Scopus, Web of Science, and Google Scholar) from the time of inception until March 2020. Results The authors search strategy yielded 3,229 citations, of which 48 eligible studies captured. 105 mutations were captured, of these, 99 were shared between Arabs and other ethnic groups, six mutations were unique to Arabs (c.92 + 2 T > G, c.-240 G > A, c.150delC, c.420dupT, deletion of 192 bp spanning exon 1, intron 1, and the first two bases of exon 2 of HBB gene, and deletion of 9.6 kb, including exon 1 and intron 2 of HBB gene). The most common HBB gene mutations among Arabs were c.93-21 G > A, c.118 C > T, c.92 + 1 G > A, c.92 + 6 T > C, c.92 + 5 G > C, c.315 + 1 G > A, and c.27dupG. Consanguinity is high among Arab patients with β-thal. Migration into Arab countries led to allelic heterogeneity among Arab patients with β-thal. Conclusion Our findings present a platform for further genetic epidemiological studies for Arab patients with β-thal.

https://www.tandfonline.com/doi/pdf/10.1080/17474086.2021.1860003

Asma Mohammed Al-Sulaiti

Papers

Drosophila as a Model Organism in Host-Pathogen Interaction Studies.

The spectrum of beta-thalassemia mutations in the 22 Arab countries: a systematic review.