The alternative pathway (AP) of complement is constantly active in plasma and can easily be activated on self surfaces and trigger local inflammation. Host cells are protected from AP attack by Factor H (FH), the main AP regulator in plasma. Although complement is known to play a role in atherosclerosis, the mechanisms of its contribution are not fully understood. Since FH via its domains 5–7 binds apoliporotein E (apoE) and macrophages produce apoE we examined how FH could be involved in the antiatherogenic effects of apoE. We used blood peripheral monocytes and THP-1 monocyte/macrophage cells which were also loaded with acetylated low-density lipoprotein (LDL) to form foam cells. Binding of FH and apoE on these cells was analyzed by flow cytometry. High-density lipoprotein (HDL)-mediated cholesterol efflux of activated THP-1 cells was measured and transcriptomes of THP-1 cells using mRNA sequencing were determined. We found that binding of FH to human blood monocytes and cholesterol-loaded THP-1 macrophages increased apoE binding to these cells. Preincubation of fluorescent cholesterol labeled THP-1 macrophages in the presence of FH increased cholesterol efflux and cholesterol-loaded macrophages displayed reduced transcription of proinflammatory/proatherogenic factors and increased transcription of anti-inflammatory/anti-atherogenic factors. Further incubation of THP-1 cells with serum reduced C3b/iC3b deposition. Overall, our data indicate that apoE and FH interact with monocytic cells in a concerted action and this interaction reduces complement activation and inflammation in the atherosclerotic lesions. By this way FH may participate in mediating the beneficial effects of apoE in suppressing atherosclerotic lesion progression.

The most frequent form of hemolytic-uremic syndrome (HUS) is associated with infections caused by Shiga-like toxin-producing Enterohaemorrhagic Escherichia coli (STEC). In rarer cases HUS can be triggered by Streptococcus pneumoniae . While production of Shiga-like toxins explains STEC-HUS, the mechanisms of pneumococcal HUS are less well-known . S. pneumoniae produces neuraminidases with activity against cell surface sialic acids that are critical for factor H-mediated complement regulation on cells and platelets. The aim of this study was to find out whether S. pneumoniae neuraminidase NanA could trigger complement activation and hemolysis in whole blood. We studied clinical S. pneumoniae isolates and two laboratory strains, a wild-type strain expressing NanA, and a NanA deletion mutant for their ability to remove sialic acids from various human cells and platelets. Red blood cell lysis and activation of complement was measured ex vivo by incubating whole blood with bacterial culture supernatants. We show here that NanA expressing S. pneumoniae strains and isolates are able to remove sialic acids from cells, and platelets. Removal of sialic acids by NanA increased complement activity in whole blood, while absence of NanA blocked complement triggering and hemolytic activity indicating that removal of sialic acids by NanA could potentially trigger pHUS.

Streptococci are a broad group of Gram-positive bacteria. This genus includes various human pathogens causing significant morbidity and mortality. Two of the most important human pathogens are Streptococcus pneumoniae (pneumococcus) and Streptococcus pyogenes (group A streptococcus or GAS). Streptococcal pathogens have evolved to express virulence factors that enable them to evade complement-mediated attack. These include factor Hbinding M (S. pyogenes) and pneumococcal surface protein C (PspC) (S. pneumoniae) proteins. In addition, S. pyogenes and S. pneumoniae express cytolysins (streptolysin and pneumolysin), which are able to destroy host cells. Sometimes, the interplay between streptococci, the complement, and antistreptococcal immunity may lead to an excessive inflammatory response or autoimmune disease. Understanding the fundamental role of the complement system in microbial clearance and the bacterial escape mechanisms is of paramount importance for understanding microbial virulence, in general, and, the conversion of commensals to pathogens, more specifically. Such insights may help to identify novel antibiotic and vaccine targets in bacterial pathogens to counter their growing resistance to commonly used antibiotics.

High-density lipoproteins (HDLs) are a group of different subpopulations of sialylated particles that have an essential role in the reverse cholesterol transport (RCT) pathway. Importantly, changes in the protein and lipid composition of HDLs may lead to the formation of particles with reduced atheroprotective properties. Here, we show that Streptococcus pneumoniae pneumolysin (PLY) and neuraminidase A (NanA) impair HDL function by causing chemical and structural modifications of HDLs. The proteomic, lipidomic, cellular, and biochemical analysis revealed that PLY and NanA induce significant changes in sialic acid, protein, and lipid compositions of HDL. The modified HDL particles have reduced cholesterol acceptor potential from activated macrophages, elevated levels of malondialdehyde adducts, and show significantly increased complement activating capacity. These results suggest that accumulation of these modified HDL particles in the arterial intima may present a trigger for complement activation, inflammatory response, and thereby promote atherogenic disease progression.

IntroductionDelusions, such as belief in conspiracy theories (CT), exist on a continuum representing clinical and subclinical populations. Some individuals are more susceptible to CT belief. Social media has allowed conspiracy theories to spread relatively unchecked. We report a previously healthy male hospitalized for delusions and reckless behavior. We analyze potential risk factors affecting this patient.Case PresentationA 54-year-old Caucasian male presents with worsening persecutory and grandiose delusions over the past 6 months. An active participant in conspiracy theory-related online forums, he believes he has sensitive information regarding the Federal Bureau of Investigation. He endorses delusions of surveillance and tracking by family members, citing these concerns prompted him to rely on public transportation and prepaid cell phones, and even trespassing on U.S. Navy property. On evaluation, the patient prompts the team to review his collection of classified evidence claiming government involvement in a global sex trafficking operation. When challenged, the patient becomes argumentative, citing social media sources. He shows no evidence of overt depression, mania, or post-traumatic stress. The patient’s level of functioning is reduced but not markedly impaired and he maintains employment. CBC, CMP, noncontrast head CT, CXR, and EKG are unremarkable. Cannabinoids are found on UTOX. He has a Positive and Negative Syndrome Scale score of 23/49 (positive), 10/49 (negative), and 31/112 (General Psychopathology), and Brown Assessment of Beliefs Scale score of 19/24.DiscussionConspiracy theories (CT) are the result of an altered perception of reality. Belief in CT correlates with negative social, health, and civic outcomes, including increased tolerance to violent and antisocial behavior. Magical thinking, trait Machiavellianism, narcissistic traits, and primary psychopathy have been shown to be significant positive predictors of belief in CT. Individuals with maladaptive perception/attribution styles may also develop cognitive distortions. Finally, intuitive thinking, as opposed to analytical thinking, is associated with CT beliefs. Social or political crises may incite elevated emotional responses, causing increased popularity of CT during times of major social or political change. Identifying these traits may be useful for clinicians providing interventions for patients with CT ideation. This patient’s presentation with delusions and nonimpaired functioning may be explained by deficits in objective reasoning as a result of maladaptive cognitive and affective response mechanisms, rather than psychotic illness.ConclusionConspiracy theories are generated as a consequence of social and political discontent and can result in a clinically significant impact on mental health and well-being. Patients with narcissistic traits and primary psychopathy are more likely to demonstrate impaired judgment related to CT.FundingNo funding