Are secondary bacterial pneumonia mortalities increased because of insufficient pro-resolving mediators?

Respiratory viral infections, including respiratory syncytial virus (RSV), parainfluenza viruses and type A and B influenza viruses, can have severe outcomes. Bacterial infections frequently follow viral infections, and influenza or other viral epidemics periodically have higher mortalities from secondary bacterial pneumonias. Most secondary bacterial infections can cause lung immunosuppression by fatty acid mediators which activate cellular receptors to manipulate neutrophils, macrophages, natural killer cells, dendritic cells and other lung immune cells. Bacterial infections induce synthesis of inflammatory mediators including prostaglandins and leukotrienes, then eventually also special pro-resolving mediators, including lipoxins, resolvins, protectins and maresins, which normally resolve inflammation and immunosuppression. Concurrent viral and secondary bacterial infections are more dangerous, because viral infections can cause inflammation and immunosuppression before the secondary bacterial infections worsen inflammation and immunosuppression. Plausibly, the higher mortalities of secondary bacterial pneumonias are caused by the overwhelming inflammation and immunosuppression, which the special pro-resolving mediators might not resolve.

Immunoregulatory natural killer cells.

This review discusses a broader scope of functional roles for NK cells. Despite the well-known cytolytic and inflammatory roles of NK cells against tumors and pathogenic diseases, extensive evidence demonstrates certain subsets of NK cells have defacto immunoregulatory effects and have a role in inducing anergy or lysis of antigen-activated T cells and regulating several autoimmune diseases. Furthermore, recent evidence suggests certain subsets of immunoregulatory NK cells can cause anergy or lysis of antigen-activated T cells to regulate hyperinflammatory diseases, including multisystem inflammatory syndrome. Several pathogens induce T cell and NK cell exhaustion and/or suppression, which impair the immune system's control of the replication speed of virulent pathogens and tumors and result in extensive antigens and antigen-antibody immune complexes, potentially inducing to some extent a Type III hypersensitivity immune reaction. The Type III hypersensitivity immune reaction induces immune cell secretion of proteinases, which can cleave specific proteins to create autoantigens which activate T cells to initiate autoimmune and/or hyperinflammatory diseases. Furthermore, pathogen induced NK cell exhaustion and/or suppression will inhibit NK cells which would have induced the anergy or lysis of activated T cells to regulate autoimmune and hyperinflammatory diseases. Autoimmune and hyperinflammatory diseases can be consequences of the dual lymphocyte exhaustion and/or suppression effects during infections, by creating autoimmune and/or hyperinflammatory diseases, while also impairing immunoregulatory lymphocytes which otherwise would have regulated these diseases.

Increased Fungal Infection Mortality Induced by Concurrent Viral Cellular Manipulations.

Certain respiratory fungal pathogen mono-infections can cause high mortality rates. Several viral pathogen mono-infections, including influenza viruses and coronaviruses including SARS-CoV-2, can also cause high mortality rates. Concurrent infections by fungal pathogens and highly manipulative viral pathogens can synergistically interact in the respiratory tract to substantially increase their mortality rates. There are at least five viral manipulations which can assist secondary fungal infections. These viral manipulations include the following: (1) inhibiting transcription factors and cytokine expressions, (2) impairing defensive protein expressions, (3) inhibiting defenses by manipulating cellular sensors and signaling pathways, (4) inhibiting defenses by secreting exosomes, and (5) stimulating glucocorticoid synthesis to suppress immune defenses by inhibiting cytokine, chemokine, and adhesion molecule production. The highest mortality respiratory viral pandemics up to now have had substantially boosted mortalities by inducing secondary bacterial pneumonias. However, numerous animal species besides humans are also carriers of endemic infections by viral and multidrug-resistant fungal pathogens. The vast multi-species scope of endemic infection opportunities make it plausible that the pro-fungal manipulations of a respiratory virus can someday evolve to enable a very high mortality rate viral pandemic inducing multidrug-resistant secondary fungal pathogen infections. Since such pandemics can quickly spread world-wide and outrun existing treatments, it would be worthwhile to develop new antifungal treatments well before such a high mortality event occurs.

Deadly interactions: Synergistic manipulations of concurrent pathogen infections potentially enabling future pandemics.

Certain mono-infections of influenza viruses and novel coronaviruses, including severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) are significant threats to human health. Concurrent infections by influenza viruses and coronaviruses increases their danger. Influenza viruses have eight manipulations capable of assisting SARS-CoV-2 and other coronaviruses, and several of these manipulations, which are not specific to viruses, can also directly or indirectly boost dangerous secondary bacterial pneumonias. The influenza virus manipulations include: inhibiting transcription factors and cytokine expression; impairing defensive protein expression; increasing RNA viral replication; inhibiting defenses by manipulating cellular sensors and signaling pathways; inhibiting defenses by secreting exosomes; stimulating cholesterol production to increase synthesized virion infectivities; increasing cellular autophagy to assist viral replication; and stimulating glucocorticoid synthesis to suppress innate and adaptive immune defenses by inhibiting cytokine, chemokine, and adhesion molecule production. Teaser: Rapidly spreading multidrug-resistant respiratory bacteria, combined with influenza virus's far-reaching cellular defense manipulations benefiting evolving SARS-CoV-2 or other coronaviruses and/or respiratory bacteria, can enable more severe pandemics or co-pandemics.

Eight influenza virus cellular manipulations which can boost concurrent SARS-CoV-2 infections to severe outcomes.

Viral pathogens in the lungs can cause severe outcomes, including acute lung injury and acute respiratory distress syndrome. Dangerous respiratory pathogens include some influenza A and B viruses, and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Unfortunately, concurrent infections of influenza virus and SARS-CoV-2 increase severe outcome probabilities. Influenza viruses have eight cellular manipulations which can assist concurrent SARS-CoV-2 viral infections. The eight cellular manipulations include: (1) viral protein binding with cellular sensors to block antiviral transcription factors and cytokine expressions, (2) viral protein binding with cell proteins to impair cellular pre-messenger ribonucleic acid splicing, (3) increased ribonucleic acid virus replication through the phosphatidylinositol 3-kinase/Akt (protein kinase B) pathway, (4) regulatory ribonucleic acids to manipulate cellular sensors and pathways to suppress antiviral defenses, (5) exosomes to transmit influenza virus to uninfected cells to weaken cellular defenses before SARS-CoV-2 infection, (6) increased cellular cholesterol and lipids to improve virion synthesis stability, quality and virion infectivity, (7) increased cellular autophagy, benefiting influenza virus and SARS-CoV-2 replications and (8) adrenal gland stimulation to produce glucocorticoids, which suppress immune cells, including reduced synthesis of cytokines, chemokines and adhesion molecules. Concurrent infections by one of the influenza viruses and SARS-CoV-2 will increase the probability of severe outcomes, and with sufficient synergy potentially enable the recurrence of tragic pandemics.

A mammalian lung's immune system minimizes tissue damage by initiating five major sequential phases of defense.

The mammalian lungs encounter several pathogens, but have a sophisticated multi-phase immune defense. Furthermore, several immune responses to suppress pulmonary pathogens can damage the airway epithelial cells, particularly the vital alveolar epithelial cells (pneumocytes). The lungs have a sequentially activated, but overlapping, five phase immune response to suppress most pathogens, while causing minimal damage to the airway epithelial cells. Each phase of the immune response may suppress the pathogens, but if the previous phase proves inadequate, a stronger phase of immune response is activated, but with an increased risk of airway epithelial cell damage. The first phase immune response involves the pulmonary surfactants, which have proteins and phospholipids with potentially sufficient antibacterial, antifungal and antiviral properties to suppress many pathogens. The second phase immune response involves the type III interferons, having pathogen responses with comparatively minimal risk of damage to airway epithelial cells. The third phase immune response involves type I interferons, which implement stronger immune responses against pathogens with an increased risk of damage to airway epithelial cells. The fourth phase immune response involves the type II interferon, interferon-γ, which activates stronger immune responses, but with considerable risk of airway epithelial cell damage. The fifth phase immune response involves antibodies, potentially activating the complement system. In summary, five major phases of immune responses for the lungs are sequentially initiated to create an overlapping immune response which can suppress most pathogens, while usually causing minimal damage to the airway epithelial cells, including the pneumocytes.

A latent pathogen infection classification system that would significantly increase healthcare safety.

Most viral, bacterial, fungal, and protozoan pathogens can cause latent infections. Latent pathogens can be reactivated from any intentional medical treatment causing immune system suppression, pathogen infections, malnutrition, stress, or drug side effects. These reactivations of latent pathogen infections can be dangerous and even lethal, especially in immuno-suppressed individuals. The latent pathogen infections in an individual can be classified and updated on a periodic basis in a four category system by whether or not an individual's immune system is damaged and by whether or not these latent infections will assist other active or latent pathogen infections. Such a classification system for latent infections by viral, bacterial, fungal, and protozoan parasite pathogens would be practical and useful and indicate whether certain medical treatments will be dangerous for transmitting or reactivating an individual's latent pathogen infections. This classification system will immediately provide latent pathogen infection status information that is potentially vital for emergency care and essential for quickly and safely selecting tissue or organ transplant donors and recipients, and it will significantly increase the safety of medical care for both patients and medical care providers.

Treatment alternatives for multidrug-resistant fungal pathogens.

Several fungal pathogens are becoming resistant to conventional fungal infection treatments, and some fungal pathogens have become multidrug-resistant. Alternative treatments include fungal vaccines, conventional or synthetic monoclonal antibody (mAb) injections, or potentially conventional or synthetic mAbs produced in vivo by injections of appropriately packaged mRNA. Specifically synthesized proteins can mask distinctive pathogenic fungal surface proteins and target pathogenic fungal proteins to stop fungal infections. Treatments could also use combinations of one or more antifungal drugs combined with direct injections or injections of packaged mRNA with instructions for patient synthesis of either the conventional or synthetic mAbs. These alternative treatments offer potentially significant advantages compared with existing treatments for fungal pathogens.

Pathogen regulatory RNA usage enables chronic infections, T-cell exhaustion and accelerated T-cell exhaustion.

Pathogens evade or disable cellular immune defenses using regulatory ribonucleic acids (RNAs), including microRNAs and long non-coding RNAs. Pathogenic usage of regulatory RNA enables chronic infections. Chronic infections, using host regulatory RNAs and/or creating pathogenic regulatory RNAs against cellular defenses, can cause T-cell exhaustion and latent pathogen reactivations. Concurrent pathogen infections of cells enable several possibilities. A first pathogen can cause an accelerated T-cell exhaustion for a second pathogen cellular infection. Accelerated T-cell exhaustion for the second pathogen weakens T-cell targeting of the second pathogen and enables a first-time infection by the second pathogen to replicate quickly and extensively. This can induce a large antibody population, which may be inadequately targeted against the second pathogen. Accelerated T-cell exhaustion can explain the relatively short median and average times from diagnosis to mortality in some viral epidemics, e.g., COVID-19, where the second pathogen can lethally overwhelm individuals' immune defenses. Alternatively, if an individual survives, the second pathogen could induce a very high titer of antigen-antibody immune complexes. If the antigen-antibody immune complex titer quickly becomes very high, it can exceed the immune system's phagocytic capability in immuno-deficient individuals, resulting in a Type III hypersensitivity immune reaction. Accelerated T-cell exhaustion in immuno-deficient individuals can be a fundamental cause of several hyperinflammatory diseases and autoimmune diseases. This would be possible when impaired follicular helper CD4+ T-cell assistance to germinal center B-cell somatic hypermutation, affinity maturation and isotype switching of antibodies results in high titers of inadequate antibodies, and this initiates a Type III hypersensitivity immune reaction with proteinase releases which express or expose autoantigens.

Concurrent infections of cells by two pathogens can enable a reactivation of the first pathogen and the second pathogen's accelerated T-cell exhaustion.

When multiple intracellular pathogens, such as viruses, bacteria, fungi and protozoan parasites, infect the same host cell, they can help each other. A pathogen can substantially help another pathogen by disabling cellular immune defenses, using non-coding ribonucleic acids and/or pathogen proteins that target interferon-stimulated genes and other genes that express immune defense proteins. This can enable reactivation of a latent first pathogen and accelerate T-cell exhaustion and/or T-cell suppression regarding a second pathogen. In a worst-case scenario, accelerated T-cell exhaustion and/or T-cell suppression regarding the second pathogen can impair T-cell functionality and allow a first-time, immunologically novel second pathogen infection to escape all adaptive immune system defenses, including antibodies. The interactions of herpesviruses with concurrent intracellular pathogens in epithelial cells and B-cells, the interactions of the human immunodeficiency virus with Mycobacterium tuberculosis in macrophages and the interactions of Toxoplasma gondii with other pathogens in almost any type of animal cell are considered. The reactivation of latent pathogens and the acceleration of T-cell exhaustion for the second pathogen can explain several puzzling aspects of viral epidemics, such as COVID-19 and their unusual comorbidity mortality rates and post-infection symptoms.

NK-cell exhaustion, B-cell exhaustion and T-cell exhaustion-the differences and similarities.

T-cell exhaustion has been extensively researched, compared with B-cell exhaustion and NK-cell exhaustion, which have received considerably less attention; and there is less of a consensus on the precise definitions of NK-cell and B-cell exhaustion. NK-cell exhaustion, B-cell exhaustion and T-cell exhaustion are examples of lymphocyte exhaustion, and they have several differences and similarities. Lymphocyte exhaustion is also frequently confused with anergy, cellular senescence and suppression, because these conditions can have significant overlapping similarities with exhaustion. An additional source of confusion is due to the fact that lymphocyte exhaustion is not a binary state, but instead has a spectrum of severity induced by different levels and duration of continuous antigenic stimulation. Concurrent multiple types of lymphocyte exhaustion are possible, and this situation is herein called poly-lymphocyte exhaustion. Poly-lymphocyte exhaustion for the same cancer or pathogen would be especially dangerous. As there are significant advantages for a pathogen by inducing poly-lymphocyte exhaustion in an immune system, there are pathogens with an evolved capability to induce poly-lymphocyte exhaustion. These pathogens may include certain manipulative viruses, bacteria, fungi and protozoan parasites.

Population structure and gene flow in the Sheepnose mussel (Plethobasus cyphyus) and their implications for conservation.

North American freshwater mussel species have experienced substantial range fragmentation and population reductions. These impacts have the potential to reduce genetic connectivity among populations and increase the risk of losing genetic diversity. Thirteen microsatellite loci and an 883 bp fragment of the mitochondrial ND1 gene were used to assess genetic diversity, population structure, contemporary migration rates, and population size changes across the range of the Sheepnose mussel (Plethobasus cyphyus). Population structure analyses reveal five populations, three in the Upper Mississippi River Basin and two in the Ohio River Basin. Sampling locations exhibit a high degree of genetic diversity and contemporary migration estimates indicate that migration within river basins is occurring, although at low rates, but there is no migration is occurring between the Ohio and Mississippi river basins. No evidence of bottlenecks was detected, and almost all locations exhibited the signature of population expansion. Our results indicate that although anthropogenic activity has altered the landscape across the range of the Sheepnose, these activities have yet to be reflected in losses of genetic diversity. Efforts to conserve Sheepnose populations should focus on maintaining existing habitats and fostering genetic connectivity between extant demes to conserve remaining genetic diversity for future viable populations.

Autism Spectrum Disorder Initiation by Inflammation-Facilitated Neurotoxin Transport.

Autism spectrum disorders have been linked to genetics, gut microbiota dysbiosis (gut dysbiosis), neurotoxin exposures, maternal allergies or autoimmune diseases. Two barriers to ingested neurotoxin transport into the central nervous system of a fetus or child are the gastrointestinal wall of the mother or child and the blood-brain barrier of the fetus or child. Inflammation from gut dysbiosis or inflammation from a disease or other agent can increase the gastrointestinal wall and the blood-brain barrier permeabilities to enable neurotoxins to reach the brain of a fetus or child. Postnatal gut dysbiosis is a particular inflammation risk for autism spectrum disorders caused by neurotoxin transport into a child's brain. An extensive gut dysbiosis or another source of inflammation such as a disease or other agent in combination with neurotoxins, including aluminum, mercury, lead, arsenic, cadmium, arsenic, organophosphates, and neurotoxic bacterial toxins and fungal toxins resulting from the gut dysbiosis, can elevate neurotoxin levels in a fetal or child brain to cause neurodevelopmental damage and initiate an autism spectrum disorder. The neurotoxins aluminum and mercury are especially synergistic in causing neurodevelopmental damage. There are three plausible causational pathways for autism spectrum disorders. They include inflammation and neurotoxin loading into the fetal brain during the prenatal neurodevelopment period, inflammation and neurotoxin loading into the brain during the postnatal neurodevelopment period or a two-stage loading of neurotoxins into the brain during both the prenatal and postnatal neurodevelopment periods.

An Alternative Explanation for Alzheimer's Disease and Parkinson's Disease Initiation from Specific Antibiotics, Gut Microbiota Dysbiosis and Neurotoxins.

The late onset neuropathologies, including Alzheimer's disease and Parkinson's disease, have become increasingly prevalent. Their causation has been linked to genetics, gut microbiota dysbiosis (gut dysbiosis), autoimmune diseases, pathogens and exposures to neurotoxins. An alternative explanatory hypothesis is provided for their pathogenesis. Virtually everyone has pervasive daily exposures to neurotoxins, through inhalation, skin contact, direct blood transmission and through the gastrointestinal tract by ingestion. As a result, every individual has substantial and fluctuating neurotoxin blood levels. Two major barriers to neurotoxin entry into the central nervous system are the blood-brain barrier and the intestinal wall, in the absence of gut dysbiosis. Inflammation from gut dysbiosis, induced by antibiotic usage, can increase the intestinal wall permeability for neurotoxins to reach the bloodstream, and also increase the blood-brain barrier permeability to neurotoxins. Gut dysbiosis, including gut dysbiosis caused by antibiotic treatments, is an especially high risk for neurotoxin entry into the brain to cause late onset neuropathologies. Gut dysbiosis has far-reaching immune system and central nervous system effects, and even a transient gut dysbiosis can act in combination with neurotoxins, such as aluminum, mercury, lead, arsenic, cadmium, selenium, manganese, organophosphate pesticides and organochlorines, to reach neurotoxin blood levels that can initiate a late onset neuropathology, depending on an individual's age and genetic vulnerability.