Innate Immune Mechanisms to Protect Against Infection at the Human Decidual-Placental Interface.

During pregnancy, the placenta forms the anatomical barrier between the mother and developing fetus. Infectious agents can potentially breach the placental barrier resulting in pathogenic transmission from mother to fetus. Innate immune responses, orchestrated by maternal and fetal cells at the decidual-placental interface, are the first line of defense to avoid vertical transmission. Here, we outline the anatomy of the human placenta and uterine lining, the decidua, and discuss the potential capacity of pathogen pattern recognition and other host defense strategies present in the innate immune cells at the placental-decidual interface. We consider major congenital infections that access the placenta from hematogenous or decidual route. Finally, we highlight the challenges in studying human placental responses to pathogens and vertical transmission using current experimental models and identify gaps in knowledge that need to be addressed. We further propose novel experimental strategies to address such limitations

Role of the capsule locus in the virulence of Bordetella pertussis

Ph.DDOCTOR OF PHILOSOPH

Pussy envy: towards post-colonial agencies of feminine corporeality

Since Independence, the Malay-Muslim woman’s body has been the site of various discursive contests imposed onto her personhood as a consequence of the conflict between the state and religious “dakwa” movement, and later, their alliance. Significantly, these changes have displayed a contradiction. On one hand, it has been made permissible on account of the Malay woman’s active acquiescence, in aspiring to the paradigm of “ideal” Muslim womanhood and its moral and familial obligations. On the other hand, various studies have documented the different layers of resistance to Islamic heteropatriarchal hegemony that Malay women exhibited through cultural and informal means. This dissertation seeks to investigate how this contradiction manifests in an impasse in the Malay woman’s body politic through a met resistance with the conscious and unconscious aspects of her corporeality. It takes the curious politicisation of the Malay vagina as an area of focus. As a reproductive organ, it has been the site of oppression and regulation, mirroring misogyny that seems to be commonplace in much of the modern world. But the Malay context also reveals a certain limit to its pacification. For this reason, the social phenomena of “bau miss V”, described as the occurrence of vaginal odour, the scent of which is unique to the individual woman; and “nasi kangkang”, a Malay folk practice that makes use of the woman’s vaginal excrements to bend the will of her husband or lover, are used as case studies wherein the vagina is presumed less as a pacified organ than it is a site of discursive contestations. Insights from the findings will be developed by way of Kristeva’s theory of the abject, to determine how insubordination to the Malay heteropatriarchy is manifested within the female body

Acute response to pathogens in the early human placenta at single-cell resolution

The placenta is a selective maternal-fetal barrier that provides nourishment and protection from infections. However, certain pathogens can attach to and even cross the placenta, causing pregnancy complications with potential lifelong impacts on the child's health. Here, we profiled at the single-cell level the placental responses to three pathogens associated with intrauterine complications—Plasmodium falciparum, Listeria monocytogenes, and Toxoplasma gondii. We found that upon exposure to the pathogens, all placental lineages trigger inflammatory responses that may compromise placental function. Additionally, we characterized the responses of fetal macrophages known as Hofbauer cells (HBCs) to each pathogen and propose that they are the probable niche for T. gondii. Finally, we revealed how P. falciparum adapts to the placental microenvironment by modulating protein export into the host erythrocyte and nutrient uptake pathways. Altogether, we have defined the cellular networks and signaling pathways mediating acute placental inflammatory responses that could contribute to pregnancy complications.</p

Acute response to pathogens in the early human placenta at single-cell resolution

The placenta is a selective maternal-fetal barrier that provides nourishment and protection from infections. However, certain pathogens can attach to and even cross the placenta, causing pregnancy complications with potential lifelong impacts on the child's health. Here, we profiled at the single-cell level the placental responses to three pathogens associated with intrauterine complications—Plasmodium falciparum, Listeria monocytogenes, and Toxoplasma gondii. We found that upon exposure to the pathogens, all placental lineages trigger inflammatory responses that may compromise placental function. Additionally, we characterized the responses of fetal macrophages known as Hofbauer cells (HBCs) to each pathogen and propose that they are the probable niche for T. gondii. Finally, we revealed how P. falciparum adapts to the placental microenvironment by modulating protein export into the host erythrocyte and nutrient uptake pathways. Altogether, we have defined the cellular networks and signaling pathways mediating acute placental inflammatory responses that could contribute to pregnancy complications.</p

Comparative Heterochromatin Profiling Reveals Conserved and Unique Epigenome Signatures Linked to Adaptation and Development of Malaria Parasites.

Heterochromatin-dependent gene silencing is central to the adaptation and survival of Plasmodium falciparum malaria parasites, allowing clonally variant gene expression during blood infection in humans. By assessing genome-wide heterochromatin protein 1 (HP1) occupancy, we present a comprehensive analysis of heterochromatin landscapes across different Plasmodium species, strains, and life cycle stages. Common targets of epigenetic silencing include fast-evolving multi-gene families encoding surface antigens and a small set of conserved HP1-associated genes with regulatory potential. Many P. falciparum heterochromatic genes are marked in a strain-specific manner, increasing the parasite's adaptive capacity. Whereas heterochromatin is strictly maintained during mitotic proliferation of asexual blood stage parasites, substantial heterochromatin reorganization occurs in differentiating gametocytes and appears crucial for the activation of key gametocyte-specific genes and adaptation of erythrocyte remodeling machinery. Collectively, these findings provide a catalog of heterochromatic genes and reveal conserved and specialized features of epigenetic control across the genus Plasmodium

COVID-19 progression and convalescence in common variable immunodeficiency patients shows incomplete adaptive responses and persistent inflammasome activation

Patients with common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, are characterized by hypogammaglobulinemia, poorly protective vaccine titers and increased susceptibility to infections. New pathogens such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), might constitute a particular threat to these immunocompromised patients since many of them experience a slower recovery and do not achieve full response to SARS-CoV-2 vaccines. To define the molecular basis of the altered immune responses caused by SARS-CoV-2 infection in CVID patients, we generated longitudinal single-cell datasets of peripheral blood immune cells along viral infection and recovery. We sampled the same individuals before, during and after SARS-CoV-2 infection to model their specific immune response dynamics while removing donor variability. We observed that COVID-19 CVID patients show defective canonical NF-κB pathway activation and dysregulated expression of BCR-related genes in naïve B cells, as well as enhanced cytotoxic activity but incomplete cytokine response in NK and T cells. Moreover, monocytes from COVID-19 CVID patients show persistent activation of several inflammasome-related genes, including the pyrin and NLRC4 inflammasomes. Our results shed light on the molecular basis of the prolonged clinical manifestations observed in these immunodeficient patients upon SARS-CoV-2 infection, which might illuminate the development of tailored treatments for COVID-19 CVID patients.We thank the CERCA Program/Generalitat de Catalunya and the Josep Carreras Foundation for institutional support. This publication is part of the Human Cell Atlas: www.humancellatlas.org/publications. This study was funded by ”la Caixa” Foundation under the grant agreement LCF/PR/HR22/52420002, Spanish Ministry of Science and Innovation (grant number PID2020-117212RB-I00/AEI/10.13038/501100011033) (E.B.), by the Wellcome Trust Grant 206194 and 108413/A/15/D (R.V.-T.), Instituto de Salud Carlos III (ISCIII), Ref. AC18/00057, associated with i-PAD project (ERARE European Union program) (E.B.), and the Chan Zuckerberg Initiative (grant 2020-216799) (R.V.-T. and E.B.). This publication has also been supported by the Unstoppable campaign of the Josep Carreras Leukaemia Foundation. We are indebted to the donors for participating in this research.N

Pussy envy: towards post-colonial agencies of feminine corporeality

Since Independence, the Malay-Muslim woman’s body has been the site of various discursive contests imposed onto her personhood as a consequence of the conflict between the state and religious “dakwa” movement, and later, their alliance. Significantly, these changes have displayed a contradiction. On one hand, it has been made permissible on account of the Malay woman’s active acquiescence, in aspiring to the paradigm of “ideal” Muslim womanhood and its moral and familial obligations. On the other hand, various studies have documented the different layers of resistance to Islamic heteropatriarchal hegemony that Malay women exhibited through cultural and informal means. This dissertation seeks to investigate how this contradiction manifests in an impasse in the Malay woman’s body politic through a met resistance with the conscious and unconscious aspects of her corporeality. It takes the curious politicisation of the Malay vagina as an area of focus. As a reproductive organ, it has been the site of oppression and regulation, mirroring misogyny that seems to be commonplace in much of the modern world. But the Malay context also reveals a certain limit to its pacification. For this reason, the social phenomena of “bau miss V”, described as the occurrence of vaginal odour, the scent of which is unique to the individual woman; and “nasi kangkang”, a Malay folk practice that makes use of the woman’s vaginal excrements to bend the will of her husband or lover, are used as case studies wherein the vagina is presumed less as a pacified organ than it is a site of discursive contestations. Insights from the findings will be developed by way of Kristeva’s theory of the abject, to determine how insubordination to the Malay heteropatriarchy is manifested within the female body

Evidence for a role of the polysaccharide capsule transport proteins in pertussis pathogenesis

Polysaccharide (PS) capsules are important virulence determinants for many bacterial pathogens. Bordetella pertussis, the agent of whooping cough, produces a surface associated microcapsule but its role in pertussis pathogenesis remained unknown. Here we showed that the B. pertussis capsule locus is expressed in vivo in murine lungs and that absence of the membrane-associated protein KpsT, involved in the transport of the PS polymers across the envelope, but not the surface-exposed PS capsule itself, affects drastically B. pertussis colonization efficacy in mice. Microarray analysis revealed that absence of KpsT in B. pertussis resulted in global down-regulation of gene expression including key virulence genes regulated by BvgA/S, the master two-component system. Using a BvgS phase-locked mutant, we demonstrated a functional link between KpsT and BvgA/S-mediated signal transduction. Whereas pull-down assays do not support physical interaction between BvgS sensor and any of the capsule locus encoded proteins, absence of KpsT impaired BvgS oligomerization, necessary for BvgS function. Furthermore, complementation studies indicated that instead of KpsT alone, the entire PS capsule transport machinery spanning the cell envelope likely plays a role in BvgS-mediated signal transduction. Our work thus provides the first experimental evidence of a role for a virulence-repressed gene in pertussis pathogenesis.Published versio

Comparative Heterochromatin Profiling Reveals Conserved and Unique Epigenome Signatures Linked to Adaptation and Development of Malaria Parasites

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