Oxygen supply and diffusion into tissues are necessary for survival. The oxygen partial pressure (pO2), which is a key component of the physiological state of an organ, results from the balance between oxygen delivery and its consumption. In mammals, oxygen is transported by red blood cells circulating in a well-organized vasculature. Oxygen delivery is dependent on the metabolic requirements and functional status of each organ. Consequently, in a physiological condition, organ and tissue are characterized by their own unique ‘tissue normoxia’ or ‘physioxia’ status. Tissue oxygenation is severely disturbed during pathological conditions such as cancer, diabetes, coronary heart disease, stroke, etc., which are associated with decrease in pO2, i.e. ‘hypoxia’. In this review, we present an array of methods currently used for assessing tissue oxygenation. We show that hypoxia is marked during tumour development and has strong consequences for oxygenation and its influence upon chemotherapy efficiency. Then we compare this to physiological pO2 values of human organs. Finally we evaluate consequences of physioxia on cell activity and its molecular modulations. More importantly we emphasize the discrepancy between in vivo and in vitro tissue and cells oxygen status which can have detrimental effects on experimental outcome. It appears that the values corresponding to the physioxia are ranging between 11% and 1% O2 whereas current in vitro experimentations are usually performed in 19.95% O2, an artificial context as far as oxygen balance is concerned. It is important to realize that most of the experiments performed in so-called normoxia might be dangerously misleading.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1582-4934.2011.01258.x

Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia

Phlebotomine sandflies transmit pathogens that affect humans and animals worldwide. We review the roles of phlebotomines in the spreading of leishmaniases, sandfly fever, summer meningitis, vesicular stomatitis, Chandipura virus encephalitis and Carrion's disease. Among over 800 species of sandfly recorded, 98 are proven or suspected vectors of human leishmaniases; these include 42 Phlebotomus species in the Old World and 56 Lutzomyia species in the New World (all: Diptera: Psychodidae). Based on incrimination criteria, we provide an updated list of proven or suspected vector species by endemic country where data are available. Increases in sandfly diffusion and density resulting from increases in breeding sites and blood sources, and the interruption of vector control activities contribute to the spreading of leishmaniasis in the settings of human migration, deforestation, urbanization and conflict. In addition, climatic changes can be expected to affect the density and dispersion of sandflies. Phlebovirus infections and diseases are present in large areas of the Old World, especially in the Mediterranean subregion, in which virus diversity has proven to be higher than initially suspected. Vesiculovirus diseases are important to livestock and humans in the southeastern U.S.A. and Latin America, and represent emerging human threats in parts of India. Carrion's disease, formerly restricted to regions of elevated altitude in Peru, Ecuador and Colombia, has shown recent expansion to non-endemic areas of the Amazon basin.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1365-2915.2012.01034.x

Phlebotomine sandflies and the spreading of leishmaniases and other diseases of public health concern

Leishmaniasis is a disease that ranges in severity from skin lesions to serious disfigurement and fatal systemic infection. WHO has classified the disease as emerging and uncontrolled and estimates that the infection results in two million new cases a year. There are 12 million people currently infected worldwide, and leishmaniasis threatens 350 million people in 88 countries. Current treatment is based on chemotherapy, which relies on a handful of drugs with serious limitations such as high cost, toxicity, difficult route of administration and lack of efficacy in endemic areas. Vaccination remains the best hope for control of all forms of the disease, and the development of a safe, effective and affordable antileishmanial vaccine is a critical global public-health priority. Extensive evidence from studies in animal models indicates that solid protection can be achieved by immunization with defined subunit vaccines or live-attenuated strains of Leishmania. However, to date, no such vaccine is available despite substantial efforts by many laboratories. The major impediment in vaccine design is the translation of data from animal models to human disease, and the transition from the laboratory to the field. Furthermore, a thorough understanding of protective immune responses and generation and maintenance of the immunological memory, the most important and least-studied aspect of antiparasitic vaccine development, during Leishmania infection is needed. This review focuses on recent findings in antileishmania vaccine field and highlights current difficulties facing vaccine development and implementation.

Leishmaniasis Vaccine: Where are We Today?

Leishmaniasis is a vector-borne neglected tropical disease associated with a spectrum of clinical manifestations, ranging from self-healing cutaneous lesions to fatal visceral infections. Among the most important questions in Leishmania research is why some species like L. donovani infect visceral organs, whereas other species like L. major remain in the skin. The determinants of visceral leishmaniasis are still poorly understood, although genomic, immunologic, and animal models are beginning to provide important insight into this disease. In this review, we discuss the vector, host, and pathogen factors that mediate the development of visceral leishmaniasis. We examine the progression of the parasite from the initial site of sand fly bite to the visceral organs and its ability to survive there. The identification of visceral disease determinants is required to understand disease evolution, to understand visceral organ survival mechanisms, and potentially to develop better interventions for this largely neglected disease.

/pdf/determinants-for-the-development-of-visceral-leishmaniasis-2h8yfikgfn.pdf

Determinants for the Development of Visceral Leishmaniasis Disease

The saliva of haematophagous arthropods contains an array of anti-haemostatic, anti-inflammatory and immunomodulatory molecules that contribute to the success of the blood meal. The saliva of haematophagous arthropods is also involved in the transmission and the establishment of pathogens in the host and in allergic responses. This survey provides a comprehensive overview of the pharmacological activity and immunogenic properties of the main salivary proteins characterised in various haematophagous arthropod species. The potential biological and epidemiological applications of these immunogenic salivary molecules will be discussed with an emphasis on their use as biomarkers of exposure to haematophagous arthropod bites or vaccine candidates that are liable to improve host protection against vector-borne diseases.

/pdf/implication-of-haematophagous-arthropod-salivary-proteins-in-3hujb7pzth.pdf

Implication of haematophagous arthropod salivary proteins in host-vector interactions

Visceral leishmaniasis (VL) is a fatal disease for humans, and no vaccine is currently available. Sand fly salivary proteins have been associated with protection against cutaneous leishmaniasis. To test whether vector salivary proteins can protect against VL, a hamster model was developed involving intradermal inoculation in the ears of 100,000 Leishmania infantum chagasi parasites together with Lutzomyia longipalpis saliva to mimic natural transmission by sand flies. Hamsters developed classical signs of VL rapidly, culminating in a fatal outcome 5–6 months postinfection. Saliva had no effect on the course of infection in this model. Immunization with 16 DNA plasmids coding for salivary proteins of Lu. longipalpis resulted in the identification of LJM19, a novel 11-kDa protein, that protected hamsters against the fatal outcome of VL. LJM19-immunized hamsters maintained a low parasite load that correlated with an overall high IFN-γ/TGF-β ratio and inducible NOS expression in the spleen and liver up to 5 months postinfection. Importantly, a delayed-type hypersensitivity response with high expression of IFN-γ was also noted in the skin of LJM19-immunized hamsters 48 h after exposure to uninfected sand fly bites. Induction of IFN-γ at the site of bite could partly explain the protection observed in the viscera of LJM19-immunized hamsters through direct parasite killing and/or priming of anti-Leishmania immunity. We have shown that immunity to a defined salivary protein (LJM19) confers powerful protection against the fatal outcome of a parasitic disease, which reinforces the concept of using components of arthropod saliva in vaccine strategies against vector-borne diseases.

/pdf/immunity-to-a-salivary-protein-of-a-sand-fly-vector-protects-519a47l61p.pdf

Immunity to a salivary protein of a sand fly vector protects against the fatal outcome of visceral leishmaniasis in a hamster model.

Allosteric regulation of oxygen delivery by RBCs may have significant effects on tumor growth. Indeed, angiogenesis, the formation of new blood vessels, is induced in growing tumors by low oxygen partial pressure. Hypoxia-inducible genes are switched on, among which are the VEGF gene and its receptors. Most important, under hypoxia, hypoxia-inducible factor 1α has a significantly prolonged half-life and up-regulates a number of hypoxia genes. Human microvascular endothelial cells (MECs), when subjected in vitro to hypoxia, align to form vessel-like structures as in the angiogenic process. We report here that, when cultured in hypoxic conditions in the presence of human RBCs loaded with a new membrane-permeant allosteric effector of Hb, myo-inositol trispyrophosphate (ITPP), endothelial cells (ECs) do not align, i.e., do not form “vessel”-like structures, because the “loaded” RBCs are capable of releasing under hypoxia more oxygen than their “normal” counterparts. Levels of VEGF and of hypoxia-inducible factor 1α, elevated in the human MECs under hypoxia, were dramatically reduced or even suppressed in the presence of the ITPP-loaded RBCs. Treatment of these ECs directly with free ITPP at different concentrations had no effect on their ability to undertake angiogenesis. Incubation with ITPP enhances the capacity of Hb to release bound oxygen, leading to higher oxygen tension in the hypoxic environment, thus inhibiting hypoxia-induced angiogenesis. These observations are suggestive of a potential in vivo role of ITPP-loaded, “low-O2-affinity” RBCs in cancer therapy.

https://www.pnas.org/content/pnas/103/42/15576.full.pdf

Suppression of hypoxia-induced HIF-1α and of angiogenesis in endothelial cells by myo-inositol trispyrophosphate-treated erythrocytes

https://www.arca.fiocruz.br/bitstream/icict/7388/1/Campanelli%20A%20P%20Chemokines%20and....pdf

Claire Crola da Silva

Papers

Immunity to a salivary protein of a sand fly vector protects against the fatal outcome of visceral leishmaniasis in a hamster model.

Suppression of hypoxia-induced HIF-1α and of angiogenesis in endothelial cells by myo-inositol trispyrophosphate-treated erythrocytes

Chemokines and chemokine receptors coordinate the inflammatory immune response in human cutaneous leishmaniasis