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This book takes a historical and anthropological approach to understanding how non-human hosts and vectors of diseases are understood, at a time when emerging infectious diseases are one of the central concerns of global health. The volume critically examines the ways in which animals have come to be framed as 'epidemic villains' since the turn of the nineteenth century. Providing epistemological and social histories of non-human epidemic blame, as well as ethnographic perspectives on its recent manifestations, the essays explore this cornerstone of modern epidemiology and public health alongside its continuing importance in today's world. Covering diverse regions, the book argues that framing animals as spreaders and reservoirs of infectious diseases - from plague to rabies to Ebola - is an integral aspect not only to scientific breakthroughs but also to the ideological and biopolitical apparatus of modern medicine. As the first book to consider the impact of the image of non-human disease hosts and vectors on medicine and public health, it offers a major contribution to our understanding of human-animal interaction under the shadow of global epidemic threat.

This systematic review aims to assess how different urbanisation patterns related to rapid urban growth, unplanned expansion, and human population density affect the establishment and distribution of Aedes aegypti and Aedes albopictus and create favourable conditions for the spread of dengue, chikungunya, and Zika viruses. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was conducted using the PubMed, Virtual Health Library, Cochrane, WHO Library Database (WHOLIS), Google Scholar, and and the Institutional Repository for Information Sharing (IRIS) databases. From a total of 523 identified studies, 86 were selected for further analysis, and 29 were finally analysed after applying all inclusion and exclusion criteria. The main explanatory variables used to associate urbanisation with epidemiological/entomological outcomes were the following: human population density, urban growth, artificial geographical space, urban construction, and urban density. Associated with the lack of a global definition of urbanisation, several studies provided their own definitions, which represents one of the study's limitations. Results were based on 8 ecological studies/models, 8 entomological surveillance studies, 7 epidemiological surveillance studies, and 6 studies consisting of spatial and predictive models. According to their focus, studies were categorised into 2 main subgroups, namely \"Aedes ecology\" and \"transmission dynamics.\" There was a consistent association between urbanisation and the distribution and density of Aedes mosquitoes in 14 of the studies and a strong relationship between vector abundance and disease transmission in 18 studies. Human population density of more than 1,000 inhabitants per square kilometer was associated with increased levels of arboviral diseases in 15 of the studies. The use of different methods in the included studies highlights the interplay of multiple factors linking urbanisation with ecological, entomological, and epidemiological parameters and the need to consider a variety of these factors for designing effective public health approaches.

Here, the presentation of lipid antigens by CD1d is shown to induce retrograde anti-inflammatory signalling in intestinal epithelial cells, resulting in the production of IL-10. Anti-inflammatory IL-10 in the intestinal mucosa Intestinal epithelial cells (IECs) are crucial to mucosal homeostasis, serving as a physical barrier and regulating the responses of mucosal immune cells to environmental factors. This paper shows that CD1d, a glycoprotein involved in the presentation of lipid antigens, induces a self-reinforcing pathway of protective mucosal immunity within the intestinal epithelium. The pathway is mediated by regulatory cytokines and heat shock proteins, and interference with any molecules involved (including CD1d, IL-10 and HSP110) is associated with uncontrolled intestinal inflammation. These findings could have relevance for inflammatory bowel disease and similar conditions. The mechanisms by which mucosal homeostasis is maintained are of central importance to inflammatory bowel disease. Critical to these processes is the intestinal epithelial cell (IEC), which regulates immune responses at the interface between the commensal microbiota and the host 1 , 2 . CD1d presents self and microbial lipid antigens to natural killer T (NKT) cells, which are involved in the pathogenesis of colitis in animal models and human inflammatory bowel disease 3 , 4 , 5 , 6 , 7 , 8 . As CD1d crosslinking on model IECs results in the production of the important regulatory cytokine interleukin (IL)-10 (ref. 9 ), decreased epithelial CD1d expression—as observed in inflammatory bowel disease 10 , 11 —may contribute substantially to intestinal inflammation. Here we show in mice that whereas bone-marrow-derived CD1d signals contribute to NKT-cell-mediated intestinal inflammation, engagement of epithelial CD1d elicits protective effects through the activation of STAT3 and STAT3-dependent transcription of IL-10, heat shock protein 110 (HSP110; also known as HSP105), and CD1d itself. All of these epithelial elements are critically involved in controlling CD1d-mediated intestinal inflammation. This is demonstrated by severe NKT-cell-mediated colitis upon IEC-specific deletion of IL-10, CD1d, and its critical regulator microsomal triglyceride transfer protein (MTP) 12 , 13 , as well as deletion of HSP110 in the radioresistant compartment. Our studies thus uncover a novel pathway of IEC-dependent regulation of mucosal homeostasis and highlight a critical role of IL-10 in the intestinal epithelium, with broad implications for diseases such as inflammatory bowel disease.

Alzheimer’s-prone mice deficient in NLRP3 or caspase-1 fail to develop learning deficits and show reduced neuropathology. Inflammasome a target in Alzheimer's disease Alzheimer's disease is associated with activation of the innate immune system. It is known that amyloid-β can activate the NLRP3 inflammasome in vitro in microglia, and here it is shown that the inflammasome has a critical role in Alzheimer's disease pathology in a mouse model in vivo . In the absence of NLRP3 or caspase-1, amyloidosis and neuropathology in mice is reduced, and cognition and associated electrophysiological parameters improved. Examination of post-mortem human Alzheimer's brains supports the link between NLRP3 and brain inflammation. Taken together, these results suggest that amyloid-β-induced activation of NLRP3 enhances the progression of Alzheimer's disease by mediating a harmful chronic inflammatory tissue post-mortem response, and that agents that block the activity of the NLRP3 inflammasome, or inflammasome-derived cytokines, might slow the progression of Alzheimer's disease. Alzheimer’s disease is the world’s most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia 1 , 2 . Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events 3 . However, it remains unknown whether NLRP3 activation contributes to Alzheimer’s disease in vivo . Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer’s disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3 −/− or Casp1 −/− mice carrying mutations associated with familial Alzheimer’s disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer’s disease, and demonstrated reduced brain caspase-1 and interleukin-1β activation as well as enhanced amyloid-β clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-β in the APP/PS1 model of Alzheimer’s disease. These results show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer’s disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.

The development of a nanoparticle RNA vaccine is reported that preferentially targets dendritic cells after systemic administration, and is shown to provide durable interferon-α-dependent antigen-specific immunity in mouse tumour models; initial results in advanced melanoma patients indicate potential efficacy in humans. An anti-cancer nanoparticulate RNA vaccine The systemic delivery of vaccine antigens into the dendritic or antigen-presenting cells of the immune system faces many technical challenges. This study reports the development of a nanoparticle RNA vaccine that preferentially targets dendritic cells after systemic administration. The vaccine consists of RNA-lipoplexes based on well-known lipid carriers; targeting is achieved by optimally adjusting the negative net charge of the nanoparticles, with no need for functionalization with molecular ligands. Intravenous administration produces durable type-I-interferon-dependent antigen-specific immunity in mouse tumour models. Initial results in patients with advanced melanoma indicate potential efficacy in humans. Virtually any tumour antigen can be encoded by RNA, so this approach is potentially more generally applicable in cancer immunotherapy. Lymphoid organs, in which antigen presenting cells (APCs) are in close proximity to T cells, are the ideal microenvironment for efficient priming and amplification of T-cell responses 1 . However, the systemic delivery of vaccine antigens into dendritic cells (DCs) is hampered by various technical challenges. Here we show that DCs can be targeted precisely and effectively in vivo using intravenously administered RNA-lipoplexes (RNA-LPX) based on well-known lipid carriers by optimally adjusting net charge, without the need for functionalization of particles with molecular ligands. The LPX protects RNA from extracellular ribonucleases and mediates its efficient uptake and expression of the encoded antigen by DC populations and macrophages in various lymphoid compartments. RNA-LPX triggers interferon-α (IFNα) release by plasmacytoid DCs and macrophages. Consequently, DC maturation in situ and inflammatory immune mechanisms reminiscent of those in the early systemic phase of viral infection are activated 2 . We show that RNA-LPX encoding viral or mutant neo-antigens or endogenous self-antigens induce strong effector and memory T-cell responses, and mediate potent IFNα-dependent rejection of progressive tumours. A phase I dose-escalation trial testing RNA-LPX that encode shared tumour antigens is ongoing. In the first three melanoma patients treated at a low-dose level, IFNα and strong antigen-specific T-cell responses were induced, supporting the identified mode of action and potency. As any polypeptide-based antigen can be encoded as RNA 3 , 4 , RNA-LPX represent a universally applicable vaccine class for systemic DC targeting and synchronized induction of both highly potent adaptive as well as type-I-IFN-mediated innate immune mechanisms for cancer immunotherapy.

The nasal commensal bacterium Staphylococcus lugdunensis produces a novel cyclic peptide antibiotic, lugdunin, that inhibits colonization by S. aureus in animal models and is associated with a significantly reduced S. aureus carriage rate in humans, suggesting that human commensal bacteria could be a valuable resource for the discovery of new antibiotics. The vast majority of systemic bacterial infections are caused by facultative, often antibiotic-resistant, pathogens colonizing human body surfaces. Nasal carriage of Staphylococcus aureus predisposes to invasive infection, but the mechanisms that permit or interfere with pathogen colonization are largely unknown. Whereas soil microbes are known to compete by production of antibiotics, such processes have rarely been reported for human microbiota. We show that nasal Staphylococcus lugdunensis strains produce lugdunin, a novel thiazolidine-containing cyclic peptide antibiotic that prohibits colonization by S. aureus , and a rare example of a non-ribosomally synthesized bioactive compound from human-associated bacteria. Lugdunin is bactericidal against major pathogens, effective in animal models, and not prone to causing development of resistance in S. aureus . Notably, human nasal colonization by S. lugdunensis was associated with a significantly reduced S. aureus carriage rate, suggesting that lugdunin or lugdunin-producing commensal bacteria could be valuable for preventing staphylococcal infections. Moreover, human microbiota should be considered as a source for new antibiotics. A novel antibiotic from the human microbiota The majority of systemic bacterial infections are caused by endogenous pathogens from human microbiota, and the opportunistic pathogen Staphylococcus aureus , commonly found in the external opening of the nostrils, is one of the most clinically important because of the prevalence of multi-drug resistant strains. The mechanisms that permit or interfere with pathogen colonization have remained unclear. This study shows that S. lugdunensis , a commensal bacterium that shares the nasal niche with S. aureus and is associated with a reduced S. aureus carriage rate in humans, produces a novel cyclic peptide antibiotic (lugdunin) that inhibits colonization by S. aureus in animal models. Lugdunin is bactericidal against major pathogens and not prone to causing development of resistance in S. aureus , suggesting that lugdunin or lugdunin-producing commensals could be valuable for preventing staphylococcal infections.

Crohn’s disease is a debilitating inflammatory bowel disease (IBD) that can involve the entire digestive tract. A single-nucleotide polymorphism (SNP) encoding a missense variant in the autophagy gene ATG16L1 (rs2241880, Thr300Ala) is strongly associated with the incidence of Crohn’s disease. Numerous studies have demonstrated the effect of ATG16L1 deletion or deficiency; however, the molecular consequences of the Thr300Ala (T300A) variant remains unknown. Here we show that amino acids 296–299 constitute a caspase cleavage motif in ATG16L1 and that the T300A variant (T316A in mice) significantly increases ATG16L1 sensitization to caspase-3-mediated processing. We observed that death-receptor activation or starvation-induced metabolic stress in human and murine macrophages increased degradation of the T300A or T316A variants of ATG16L1, respectively, resulting in diminished autophagy. Knock-in mice harbouring the T316A variant showed defective clearance of the ileal pathogen Yersinia enterocolitica and an elevated inflammatory cytokine response. In turn, deletion of the caspase-3-encoding gene, Casp3 , or elimination of the caspase cleavage site by site-directed mutagenesis rescued starvation-induced autophagy and pathogen clearance, respectively. These findings demonstrate that caspase 3 activation in the presence of a common risk allele leads to accelerated degradation of ATG16L1, placing cellular stress, apoptotic stimuli and impaired autophagy in a unified pathway that predisposes to Crohn’s disease. The Crohn’s disease risk-conferring T300A variant in the autophagy protein ATG16L1 increases its sensitivity to caspase-3-mediated cleavage; this decreases the induction of autophagy in response to metabolic stress or pathogen infection, leading to increased secretion of inflammatory cytokines. The genetics of Crohn's disease The Thr 300-to-Ala (T300A) polymorphism in the autophagy gene ATG16L1 has been recognized as a significant susceptibility factor for Crohn's disease, a chronic inflammatory bowel disease that is emerging as a significant health problem in industrialized countries. This study demonstrates that Thr 300 resides at the P1′ position of a caspase-cleavage site in human ATG16L, where it increases ATG16L1 sensitivity to caspase-3-mediated cleavage. This decreases the induction of autophagy in response to metabolic stress or death receptor stimulation leading to increased secretion of inflammatory cytokines. These observations raise the possibility that therapeutic inhibition of caspase 3 activation pathways may restore autophagy and gut homeostasis in part by stabilizing ATG16L1.

Variation in ATG16L1, a protein involved in autophagy, confers risk for Crohn’s disease, but mice with hypomorphic ATG16L1 activity do not develop spontaneous intestinal inflammation; this study shows that autophagy compensates for endoplasmic reticulum stress — common in inflammatory bowel disease epithelium — specifically in Paneth cells, with Crohn’s-disease-like inflammation of the ileum originating from this cell type when both pathways are compromised. Inflammation in Crohn's disease Variations in ATG16L1 — a protein involved in autophagy — are risk factors for Crohn's disease, but although mice homozygous for a common ATG16L1 risk allele show abnormal Paneth cell function, they do not develop intestinal inflammation as might be expected. Richard Blumberg and colleagues show that impairment of either autophagy or the unfolded protein response within Paneth cells results in each other's compensatory engagement, but that colitis develops only when both pathways are impaired. This work highlights pharmacological augmentation of autophagy as a possible therapeutic approach to controlling intestinal inflammation. The recognition of autophagy related 16-like 1 ( ATG16L1 ) as a genetic risk factor has exposed the critical role of autophagy in Crohn’s disease 1 . Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity, causes Paneth cell dysfunction 2 , 3 . As Atg16l1 HM mice do not develop spontaneous intestinal inflammation, the mechanism(s) by which ATG16L1 contributes to disease remains obscure. Deletion of the unfolded protein response (UPR) transcription factor X-box binding protein-1 ( Xbp1 ) in intestinal epithelial cells, the human orthologue of which harbours rare inflammatory bowel disease risk variants, results in endoplasmic reticulum (ER) stress, Paneth cell impairment and spontaneous enteritis 4 . Unresolved ER stress is a common feature of inflammatory bowel disease epithelium 4 , 5 , and several genetic risk factors of Crohn’s disease affect Paneth cells 2 , 4 , 6 , 7 , 8 , 9 . Here we show that impairment in either UPR ( Xbp1 ΔIEC ) or autophagy function ( Atg16l1 ΔIEC or Atg7 ΔIEC ) in intestinal epithelial cells results in each other’s compensatory engagement, and severe spontaneous Crohn’s-disease-like transmural ileitis if both mechanisms are compromised. Xbp1 ΔIEC mice show autophagosome formation in hypomorphic Paneth cells, which is linked to ER stress via protein kinase RNA-like endoplasmic reticulum kinase (PERK), elongation initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol requiring enzyme 1α (IRE1α)-regulated NF-κB activation and tumour-necrosis factor signalling, which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1α activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-κB overactivation and intestinal epithelial cell death. ER stress, autophagy induction and spontaneous ileitis emerge from Paneth-cell-specific deletion of Xbp1 . Genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn’s disease as a specific disorder of Paneth cells.

The accumulation of DNA in the cytosol serves as a key immunostimulatory signal associated with infections, cancer and genomic damage 1 , 2 . Cytosolic DNA triggers immune responses by activating the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway 3 . The binding of DNA to cGAS activates its enzymatic activity, leading to the synthesis of a second messenger, cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) 4 – 7 . This cyclic dinucleotide (CDN) activates STING 8 , which in turn activates the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), promoting the transcription of genes encoding type I interferons and other cytokines and mediators that stimulate a broader immune response. Exogenous 2′3′-cGAMP produced by malignant cells 9 and other CDNs, including those produced by bacteria 10 – 12 and synthetic CDNs used in cancer immunotherapy 13 , 14 , must traverse the cell membrane to activate STING in target cells. How these charged CDNs pass through the lipid bilayer is unknown. Here we used a genome-wide CRISPR-interference screen to identify the reduced folate carrier SLC19A1, a folate–organic phosphate antiporter, as the major transporter of CDNs. Depleting SLC19A1 in human cells inhibits CDN uptake and functional responses, and overexpressing SLC19A1 increases both uptake and functional responses. In human cell lines and primary cells ex vivo, CDN uptake is inhibited by folates as well as two medications approved for treatment of inflammatory diseases, sulfasalazine and the antifolate methotrexate. The identification of SLC19A1 as the major transporter of CDNs into cells has implications for the immunotherapeutic treatment of cancer 13 , host responsiveness to CDN-producing pathogenic microorganisms 11 and—potentially—for some inflammatory diseases. A genome-wide CRISPR-interference screen is used to identify the reduced folate carrier SLC19A1 as the major transporter of cyclic dinucleotides in human cells, with potential roles in immunotherapeutic treatment of cancer, immune responses to pathogens and inflammatory diseases.

Gain of MEKK3 signalling is shown to cause cerebral cavernous malformations (CCMs) via activation of the target genes Klf2 and Klf4 ; endothelial-specific loss of MEKK3, KLF2 or KLF4 prevents lesion formation and lethality in a mouse CCM model. Genetic rescue of cerebral cavernous malformations Mark Kahn and colleagues identify a causal mechanism for the development of cerebral cavernous malformations (CCMs) — vascular malformations that cause stroke and seizures. The CCM complex is known to regulate MEKK3 during heart development. Here the authors show that gain of MEKK3 signalling is causal to CCM development via activating the MEKK3 target genes Klf2 and Klf4 . Endothelial-specific loss of MEKK3, KLF2 or KLF4 rescues lethality in a mouse CCM model. Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals 1 . CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex 2 . How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho 3 , 4 , SMAD 5 and Wnt/β-catenin 6 ) and processes such as endothelial–mesenchymal transition (EndMT) 5 proposed to have causal roles. CCM2 binds to MEKK3 (refs 7 , 8 , 9 , 10 , 11 ), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development 12 . Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4 , as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3 ), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.