The Immune Response to Respiratory Viruses: From Start to Memory

Biomedical research has long strived to improve our understanding of the immune response to respiratory viral infections, an effort that has become all the more important as we live through the consequences of a pandemic. The disease course of these infections is shaped in large part by the actions of various cells of the innate and adaptive immune systems. While these cells are crucial in clearing viral pathogens and establishing long-term immunity, their effector mechanisms may also escalate into excessive, tissue-destructive inflammation detrimental to the host. In this review, we describe the breadth of the immune response to infection with respiratory viruses such as influenza and respiratory syncytial virus. Throughout, we focus on the host rather than the pathogen and try to describe shared patterns in the host response to different viruses. We start with the local cells of the airways, onto the recruitment and activation of innate and adaptive immune cells, followed by the establishment of local and systemic memory cells key in protection against reinfection. We end by exploring how respiratory viral infections can predispose to bacterial superinfection.

Inhibiting inflammasome; the possible mechanisms of action of azithromycin against COVID-19?

Cytokine storm and destructive inflammation in the severe form of COVID-19 lead to acute respiratory distress syndrome (ARDS)/acute lung injury (ALI), and dysfunction of several different body organs in patients. SARS-CoV-2 contains all inflammasome-activating proteins belonging to SARS-CoV and MERS-CoV viruses. Macrolides are known to possess immunomodulatory properties. Given the desirable results of azithromycin treatment for patients with a severe case of COVID-19, based on studies, it could be concluded that the immunomodulatory properties of azithromycin to inhibit inflammasome can help the treatment of patients with this disease.

Supralevator Abscess Complicated by Necrotic Fasciitis of Peritoneum, Genitalia, Anterior Abdominal Wall and Retroperitoneum.

A supralevator anorectal abscess may lead to a rare clinical complication, such as perineal necrotizing fasciitis. A 57-year-old man was admitted on an emergency basis with evidence of a deep anorectal abscess of 5-day duration. The clinical presentation involved an unbounded purulent destructive inflammation spreading onto the adjacent areas, with the development of a septic condition. Following a short preparation, a radical surgical debridement of a subfascial purulent necrotic phlegmon of the pelvic space was performed. Since the lower part of the abdomen, retroperitoneum and scrotum were involved, 4 additional subsequent necrectomies were performed at 48-hour intervals. The aggressive radical operative treatment and the combined intensive therapy were the main contributors to the favorable outcome of the disease.

Human variation in gingival inflammation

Oral commensal bacteria actively participate with gingival tissue to maintain healthy neutrophil surveillance and normal tissue and bone turnover processes. Disruption of this homeostatic host–bacteria relationship occurs during experimental gingivitis studies where it has been clearly established that increases in the bacterial burden increase gingival inflammation. Here, we show that experimental gingivitis resulted in three unique clinical inflammatory phenotypes (high, low, and slow) and reveal that interleukin-1β, a reported major gingivitis-associated inflammatory mediator, was not associated with clinical gingival inflammation in the slow response group. In addition, significantly higher levels of Streptococcus spp. were also unique to this group. The low clinical response group was characterized by low concentrations of host mediators, despite similar bacterial accumulation and compositional characteristics as the high clinical response group. Neutrophil and bone activation modulators were down-regulated in all response groups, revealing novel tissue and bone protective responses during gingival inflammation. These alterations in chemokine and microbial composition responses during experimental gingivitis reveal a previously uncharacterized variation in the human host response to a disruption in gingival homeostasis. Understanding this human variation in gingival inflammation may facilitate the identification of periodontitis-susceptible individuals. Overall, this study underscores the variability in host responses in the human population arising from variations in host immune profiles (low responders) and microbial community maturation (slow responders) that may impact clinical outcomes in terms of destructive inflammation.

The Pathogenesis of Neurotrauma Indicates Targets for Neuroprotective Therapies

: The spinal cord injury (SCI) initiates an extraordinarily protracted disease with 3 phases; acute, inflammatory and resolution that are restricted to the cavity of injury (COI) or arachnoiditis by a unique CNS reaction against the severity of destructive inflammation. While the severity of inflammation involving the white matter is fueled by a potently immunogenic activity of damaged myelin, its sequestration in the COI and its continuity with the cerebrospinal fluid of the subdural space allows for anti-inflammatory therapeutics infused subdurally to inhibit phagocytic macrophage infiltration and thus provide neuroprotection. The role of astrogliosis in containing and ultimately in eliminating severe destructive inflammation post-trauma appears obvious but is not yet sufficiently understood to use in therapeutic neuroprotective and neuroregenerative strategies. An apparent anti-inflammatory activity of reactive astrocytes is paralleled by their active role in removing excess edema fluid in blood brain barrier damaged by inflammation. Recently elucidated pathogenesis of neurotrauma including SCI, traumatic brain injury (TBI) and of stroke, calls for the following principal therapeutic steps in its treatment leading to recovery of neurologic function: (1) inhibition and elimination of destructive inflammation from the COI with accompanying reduction of vasogenic edema, (2) insertion into the COI of a functional bridge supporting the crossing of regenerating axons, (3) enabling regeneration of axons to their original synaptic targets by a temporary safe removal of myelin in targeted areas of white matter, (4) in vivo, systematic monitoring of the consecutive therapeutic steps. The focus of this paper is on the therapeutic step 1.

Delving Into the Origin of Destructive Inflammation in COVID-19: A Betrayal of Natural Host Defense Peptides?

In contrast to other pathogenic agents that directly destroy host cells and tissues, the lethal power of SARS-CoV-2 resides in the over-reactive immune response triggered by this virus. Based on numerous evidences indicating that the lipid composition of host membranes is dramatically affected by COVID-19, and in the fact that our endogenous antimicrobial peptides (AMPs) are sensitive to the membrane composition of pathogenic agents, we propose that such destructive immune response is due to the direct action of AMPs. In a scenario where most host cell membranes are dressed by a pathogenic lipid composition, AMPs can indiscriminately attack them. This is why we use the “AMP betrayal” term to describe this mechanism. Previously proposed cytokine/bradykinin storm mechanisms are not incompatible with this new proposal. Interestingly, the harmful action of AMPs could be prevented by new therapies aimed to reestablish the lipid composition or to inhibit the action of specific peptides.

Immunology and Pathology in Ocular Drug Development

Clear vision is dependent on features that protect the anatomical integrity of the eye (cornea and sclera) and those that contribute to internal ocular homeostasis by conferring hemangiogenic (avascular tissues and antiangiogenic factors), lymphangiogenic (lack of draining lymphatics), and immunologic (tight junctions that form blood–ocular barriers, immunosuppressive cells, and modulators) privileges. The later examples are necessary components that enable the eye to maintain an immunosuppressive environment that responds to foreign invaders in a deviated manner, minimizing destructive inflammation that would impair vision. These conditions allowed for the observations made by Medawar, in 1948, of delayed rejection of allogenic tissue grafts in the anterior chamber of mouse eye and permit the sequestration of foreign invaders (eg, Toxoplasma gondii) within the retina of healthy individuals. Yet successful development of intraocular drugs (biologics and delivery devices) has been stymied by adverse ocular pathology, much of which is driven by immune pathways. The eye can be intolerant of foreign protein irrespective of delivery route, and endogenous ocular cells have remarkable plasticity when recruited to preserve visual function. This article provides a review of current understanding of ocular immunology and the potential role of immune mechanisms in pathology observed with intraocular drug delivery.

Structure of the vasculitides observed in the Clinic of Rheumatology

Systemic vasculitides are a heterogenic group of disorders characterized by destructive inflammation and fibrinoid necrosis of the vascular wall, vessel occlusion and tissue ischemia. Vasculitides presenting with necrosis are included in neither of the contemporary classifications, even though this type of vascular pathology is the one with the most dramatic manifestations in rheumatology. There have been no analyses of the nosological association, clinical features and therapeutic management of the vasculitides with necrosis in the pertinent literature. The aim of the present study was to analyze vasculitides in the Bulgarian population in terms of their nosological association; to examine the portion that ANCA-associated vasculitides represent out of all vasculitic syndromes on the one hand, and to make an analysis of the vasculitides with necrosis according to their nosological association on the other. In the present study, we included 388 patients with vasculitis, 251 of whom were female and 137 male. We conducted a prospective and retrospective analysis which covered the patients with vasculitis who were admitted to the Clinic of Rheumatology over the period 2009-2018. ANCA-associated vasculitides were the most often diagnosed vasculitides in the Clinic of Rheumatology. Vasculitic manifestations over the course of connective tissue diseases (most often systemic lupus erythematosus and systemic sclerosis) were the second most common group. Life-threatening cases of vasculitis with necrosis were mainly the result of flares of different connective tissue diseases. The major necrotizing vasculitides (Wegener’s granulomatosis and microscopic polyangiitis) were responsible for 12.6% of the cases of vasculitis with necrosis. In order to establish the correct diagnosis and start the suitable treatment, it is of vital importance to recognize the different vasculitic syndromes and their wide differential diagnosis. Most of them respond well to the currently available therapeutic options, especially if the correct diagnosis has been established early.

Neuroprotective Effect of Subdural Infusion of Serp-1 in Spinal Cord Trauma

Spinal cord injury (SCI) initiates a severe, destructive inflammation with pro-inflammatory, CD68+/CD163−, phagocytic macrophages infiltrating the area of necrosis and hemorrhage by day 3 and persisting for the next 16 weeks. Inhibition of macrophage infiltration of the site of necrosis that is converted into a cavity of injury (COI) during the first week post-SCI, should limit inflammatory damage, shorten its duration and result in neuroprotection. By sustained subdural infusion we administered Serp-1, a Myxoma virus-derived immunomodulatory protein previously shown to improve neurologic deficits and inhibit macrophage infiltration in the COI in rats with the balloon crush SCI. Firstly, in a 7 day long study, we determined that the optimal dose for macrophage inhibition was 0.2 mg/week. Then, we demonstrated that a continuous subdural infusion of Serp-1 for 8 weeks resulted in consistently accelerated lowering of pro-inflammatory macrophages in the COI and in their almost complete elimination similar to that previously observed at 16 weeks in untreated SCI rats. The macrophage count in the COI is a quantitative test directly related to the severity of destructive inflammation initiated by the SCI. This test has consistently demonstrated anti-inflammatory effect of Serp-1 interpreted as neuroprotection, the first and necessary step in a therapeutic strategy in neurotrauma.