Biofilm exopolysaccharides alter sensory-neuron-mediated sickness during lung infection.

Infections of the lung cause observable sickness thought to be secondary to inflammation. Signs of sickness are crucial to alert others via behavioral-immune responses to limit contact with contagious individuals. Gram-negative bacteria produce exopolysaccharide (EPS) that provides microbial protection; however, the impact of EPS on sickness remains uncertain. Using genome-engineered Pseudomonas aeruginosa (P. aeruginosa) strains, we compared EPS-producers versus non-producers and a virulent Escherichia coli (E. coli) lung infection model in male and female mice. EPS-negative P. aeruginosa and virulent E. coli infection caused severe sickness, behavioral alterations, inflammation, and hypothermia mediated by TLR4 detection of the exposed lipopolysaccharide (LPS) in lung TRPV1+ sensory neurons. However, inflammation did not account for sickness. Stimulation of lung nociceptors induced acute stress responses in the paraventricular hypothalamic nuclei by activating corticotropin-releasing hormone neurons responsible for sickness behavior and hypothermia. Thus, EPS-producing biofilm pathogens evade initiating a lung-brain sensory neuronal response that results in sickness.

A B1a-natural IgG-neutrophil axis is impaired in viral- and steroid-associated aspergillosis.

The lung naturally resists Aspergillus fumigatus (Af) in healthy individuals, but multiple conditions can disrupt this resistance, leading to lethal invasive infections. Core processes of natural resistance and its breakdown are undefined. We investigated three distinct conditions predisposing to lethal aspergillosis-severe SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, influenza A viral pneumonia, and systemic corticosteroid use-in human patients and murine models. We found a conserved and essential coupling of innate B1a lymphocytes, Af-binding natural immunoglobulin G antibodies, and lung neutrophils. Failure of this axis concealed Af from neutrophils, allowing rapid fungal invasion and disease. Reconstituting the axis with immunoglobulin therapy reestablished resistance, thus representing a realistic pathway to repurpose currently available therapies. Together, we report a vital host resistance pathway that is responsible for protecting against life-threatening aspergillosis in the context of distinct susceptibilities.

Innate Receptors Expression by Lung Nociceptors: Impact on COVID-19 and Aging.

The lungs are constantly exposed to non-sterile air which carries harmful threats, such as particles and pathogens. Nonetheless, this organ is equipped with fast and efficient mechanisms to eliminate these threats from the airways as well as prevent pathogen invasion. The respiratory tract is densely innervated by sensory neurons, also known as nociceptors, which are responsible for the detection of external stimuli and initiation of physiological and immunological responses. Furthermore, expression of functional innate receptors by nociceptors have been reported; however, the influence of these receptors to the lung function and local immune response is poorly described. The COVID-19 pandemic has shown the importance of coordinated and competent pulmonary immunity for the prevention of pathogen spread as well as prevention of excessive tissue injury. New findings suggest that lung nociceptors can be a target of SARS-CoV-2 infection; what remains unclear is whether innate receptor trigger sensory neuron activation during SARS-CoV-2 infection and what is the relevance for the outcomes. Moreover, elderly individuals often present with respiratory, neurological and immunological dysfunction. Whether aging in the context of sensory nerve function and innate receptors contributes to the disorders of these systems is currently unknown. Here we discuss the expression of innate receptors by nociceptors, particularly in the lungs, and the possible impact of their activation on pulmonary immunity. We then demonstrate recent evidence that suggests lung sensory neurons as reservoirs for SARS-CoV-2 and possible viral recognition via innate receptors. Lastly, we explore the mechanisms by which lung nociceptors might contribute to disturbance in respiratory and immunological responses during the aging process.

Androgen Therapy in Male Patients Suffering from Type 2 Diabetes: A Review of Benefits and Risks.

BACKGROUND: The current estimated numbers of patients with Type 2 Diabetes (T2D) is believed to be close to 10% of the whole populations of many geographical regions, causing serious concerns over the resulting elevated morbidity and mortality as well as the impact on health care systems around the world. In addition to negatively affecting the quality of life, diabetes is associated with cardiovascular and cerebrovascular complications, indicating that appropriate drug therapy should not only deal with metabolic dysfunction but also protect the vascular system, kidney function and skeletal muscle mass from the effects of the epigenetic changes induced by hyperglycaemia. OBJECTIVE: To provide an insight into the management of hypogonadism associated with T2D, this review focuses on clinical observations related to androgen therapy in qualified diabetic patients, and discusses the lines of evidence for its benefits and risks. The potential interactions of testosterone with medicines used by patients with T2D will also be discussed. CONCLUSION: From recent clinical findings, it became evident that a considerable percentage of patients suffering from T2D manifested low serum testosterone and experienced diminished sexual activity, as well as reduced skeletal muscle mass and lower bone density. Although there are some controversies, Testosterone Replacement Therapy (TRT) for this particular population of patients appears to be beneficial overall only if it is implemented carefully and monitored regularly.

Are SGLT2 inhibitors joining the mainstream therapy for diabetes type 2?

BACKGROUND: Conventional therapies to prevent type 2 diabetes mellitus (T2DM) complications are only partially effective. Therefore, new therapeutic approaches leading to additional risk reduction are required. While many anti-diabetic medications have been prescribed world-wide for controlling T2DM over the past half-century, sodium-glucose co-transporter-2 (SGLT2) inhibitors are relatively new. In addition to their plasma glucose lowering effect, SGLT2 inhibitors have been shown to reduce considerably cardiovascular mortality rate in patients with T2DM. AIM: Since, a risk and benefit analysis of co-administration of SGLT2 inhibitors and other anti-diabetic agents in patients who suffer from hypertension, heart failure or renal deficiency is currently lacking, the main objective of this article is to review the recent literature and provide the health care professionals with evidence-based opinions on the subject. CONCLUSION: SGLT2 inhibitors have relatively safe profiles and can efficiently decrease HbA1c as well as fasting and postprandial glucose levels. Furthermore, SGLT2 inhibitors administrations are not associated with significant hypoglycemic episodes or weight gain. Thus, combination of SGLT2 inhibitors and other less harmful anti-diabetic medicines could be considered if there is no any contraindication.