Blowing the Whistle at the FDA, Jan 2001, exposing Dearborn and how OspA causes immunosuppression rather than, "was a vaccine."

01 Oct 2017


File List, RICO

1988 Steere says Lyme is like a B cell leukemia

Assoc Blogs-n-Webs:




Fungal Exosomes Inhibit Apoptosis

IDSA: "Vaccines serve the mfgs, not their victims"


BlumenthalAntiTrust Lawsuit

Exosomes, Blebs


CDC Admits Fraud, 2016
Dattwyler, 1988
Golightly, 1988
Dressler, 1994
BarbourFish, 1993
Dearborn, 1994

Pathogenic Fungi

Bush's warcrimes, Oct 2000





Short Summary of failed fungal vaccines and immunosuppression caused by LYMErix:

THE MECHANICS OF FUNGAL-ANTIGEN-RELATED IMMUNE SUPPRESSION-  Brought to you as a summary of the available science.  

1) Tolerance Induced by the Lipopeptide Pam3Cys [OspA] Is Due to Ablation of IL-1R-Associated Kinase-11  

"Although a single ligation of TLRs induces responses such as TNF production, repeated ligation will lead to a loss of response, i.e., the cells become tolerant."


2) "Borrelia burgdorferi-Induced Tolerance as a Model of Persistence via Immunosuppression" - 

"In summary, we characterized tolerance induced by B. burgdorferi, describing a model of desensitization which might mirror the immunosuppression recently attributed to the persistence of Borrelia in immunocompetent hosts."


3) Mycobacterium tuberculosis LprG (Rv1411c): A Novel TLR-2 Ligand That Inhibits Human Macrophage Class II MHC Antigen Processing1    

The Journal of Immunology, 2004, 173: 2660-2668.
Copyright © 2004 by The American Association of Immunologists

 "Signaling through TLR-2 by lipoproteins may represent a double-edged sword for host responses to chronic intracellular pathogens such as M. tuberculosis. Short-term signaling through TLR-2 activates macrophages and initiates acute inflammation that may help control initial infection. In contrast, prolonged TLR-2 signaling in macrophages results in down-regulation of certain critical immune functions, such as MHC-II Ag processing. M. tuberculosis infects, survives, and persists in macrophages. The ability of M. tuberculosis to survive acute inflammation positions the bacilli to take advantage, through secretion of lipoproteins such as LprG and LpqH, of this down-regulation of macrophage immune function." 

4) Lipopolysaccharide Binding Protein Binds to Triacylated and Diacylated Lipopeptides and Mediates Innate Immune Responses1

"Lipoproteins and lipopeptides have been identified in a large number of microorganisms, the most prominent ones being mycobacteria, mycoplasms, and spirochetes. They have been found to exhibit both a strong innate inflammatory response in the host and an enduring adaptive immune response in mammalian hosts (16). The strong proinflammatory capacities of lipoproteins were first described for outer surface proteins A and B of Borrelia burgdorferi, which are also highly immunogenic (17) and have lately been the basis for a Lyme disease vaccine development (18). These compounds exhibit an triacylated lipid anchor structure comprising an N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteinyl (Pam3Cys) moiety at the N terminus (19), a feature that was previously described for the Braun lipoprotein from Escherichia coli (20). Because the N-terminal Pam3Cys modification is essential for immunoactivation caused by lipoproteins of B. burgdorferi as well as of another spirochete, Treponema pallidum (21), subsequent studies investigating immune responses to spirochetes used synthetic lipopeptides (22). The Pam3Cys moiety was also reported to be present in cytokine-inducing lipoproteins of Mycobacterium and Mycoplasma spp. (23, 24); thus, it can be regarded as a highly conserved molecular motif among different classes of bacteria. In Mycoplasma fermentans, the presence of a macrophage stimulating lipopeptide, termed 2-kDa macrophage-activating lipopeptide (MALP-2), was observed, being stimulatory active at picomolar concentrations (25). This compound, in contrast to the predominant lipopeptide structures present in lipoproteins of E. coli, B. burgdorferi, and mycobacteria, lacks the N-palmitoyl group, thus containing a diacylated (Pam2Cys) lipid anchor structure at the N terminus. Following studies revealed the presence of closely related compounds in other Mycoplasma spp. (26).."   

"Toll-like receptors (TLRs) 2 and 4 are signal transducers for lipopolysaccharide, the major proinflammatory constituent in the outer membrane of Gram-negative bacteria. We observed that membrane lipoproteins/lipopeptides from Borrelia burgdorferi, Treponema pallidum, and Mycoplasma fermentans activated cells heterologously expressing TLR2 but not those expressing TLR1 or TLR4. These TLR2-expressing cells were also stimulated by living motile B. burgdorferi, suggesting that TLR2 recognition of lipoproteins is relevant to natural Borrelia infection. Importantly, a TLR2 antibody inhibited bacterial lipoprotein/lipopeptide-induced tumor necrosis factor release from human peripheral blood mononuclear cells, and TLR2-null Chinese hamster macrophages were insensitive to lipoprotein/lipopeptide challenge. The data suggest a role for the native protein in cellular activation by these ligands. In addition, TLR2-dependent responses were seen using whole Mycobacterium avium and Staphylococcus aureus, demonstrating that this receptor can function as a signal transducer for a wide spectrum of bacterial products. We conclude that diverse pathogens activate cells through TLR2 and propose that this molecule is a central pattern recognition receptor in host immune responses to microbial invasion."



It is interesting that in this Tg mouse model, antigen-presenting cells (macrophages and dendritic and B cells) rather than T cells provide the major source of elevated HIV-1 production. Furthermore, we have recently demonstrated that known TLR agonists such as LPS, monosylated phosphatidylinositol, CpG, and S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser-Lys4-OH, trihydrochloride (Pam3Cys) stimulate increased levels of HIV-1 transcripts as well as production of p24 (a capsid protein encoded by the gag gene) by Tg spleen cells in vitro [15 , 16 ].

In the present report, we show that after tolerization with TLR2, TLR4, or TLR9 ligands, Tg cells unexpectedly display enhanced HIV-1 gene and protein expression after restimulation in vitro despite dramatic reductions in proinflammatory cytokine production. Moreover, Tg mice tolerized in vivo with LPS or Pam3Cys show increased levels of plasma p24, whereas TNF-{alpha} production is markedly diminished in the same animals. This overexpression of HIV-1 genes following TLR reprogramming may reflect a mechanism used by the virus to escape the effects of microbial-induced tolerance during natural infection in vivo.


The induction of Toll-like receptor tolerance enhances rather than suppresses HIV-1 gene expression in transgenic mice.

Immunobiology Section, Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20982, USA.

Microbial-induced proinflammatory pathways are thought to play a key role in the activation of human immunodeficiency virus type 1 (HIV-1) gene expression. The induction of Toll-like receptor (TLR) tolerance leads to a complex reprogramming in the pattern of inflammatory gene expression and down-modulates tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1, and IL-6 production. Using transgenic (Tg) mice that incorporate the entire HIV-1 genome, including the long-terminal repeat, we have previously demonstrated that a number of different TLR ligands induce HIV-1 gene expression in cultured splenocytes as well as purified antigen-presenting cell populations. Here, we have used this model to determine the effect of TLR-mediated tolerance as an approach to inhibiting microbial-induced viral gene expression in vivo. Unexpectedly, Tg splenocytes and macrophages, rendered tolerant in vitro to TLR2, TLR4, and TLR9 ligands as assessed by proinflammatory cytokine secretion and nuclear factor-kappaB activation, showed enhanced HIV-1 p24 production. A similar enhancement was observed in splenocytes tolerized and then challenged with heterologous TLR ligands. Moreover, TLR2- and TLR4-homotolerized mice demonstrated significantly increased plasma p24 production in vivo despite lower levels of TNF-alpha. Together, these results demonstrate that HIV-1 expression is enhanced in TLR-reprogrammed host cells, possibly reflecting a mechanism used by the virus to escape the effects of microbial-induced tolerance during natural infection in vivo.


See?  That's a major F-up, that might have been investigated sooner, had the Yale Lyme crooks told the truth about LYMErix in the mid-1990s when they were having their fake OspA (Pam3Cys) trials, for which the changed the diagnostic standard for Lyme.  This is in addition to the fact that OspA was never shown to prevent Lyme in lab animals.

That's 5 reports that showed OspA failed in animals, 3 reports that showed fungal antigens failed in tuberculosis vaccines, plus the 8 reports you see here.


6) AUGUST, 2008:

Human immunodeficiency virus infection alters tumor necrosis factor alpha production via Toll-like receptor-dependent pathways in alveolar macrophages and U1 cells.

Center for HIV/AIDS Care and Research, Boston University School of Medicine, Boston, MA 02118-2393, USA.

Human immunodeficiency virus (HIV)-positive persons are predisposed to pulmonary infections, even after receiving effective highly active antiretroviral therapy. The reasons for this are unclear but may involve changes in innate immune function. HIV type 1 infection of macrophages impairs effector functions, including cytokine production. We observed decreased constitutive tumor necrosis factor alpha (TNF-alpha) concentrations and increased soluble tumor necrosis factor receptor type II (sTNFRII) in bronchoalveolar lavage fluid samples from HIV-positive subjects compared to healthy controls. Moreover, net proinflammatory TNF-alpha activity, as measured by the TNF-alpha/sTNFRII ratio, decreased as HIV-related disease progressed, as manifested by decreasing CD4 cell count and increasing HIV RNA (viral load). Since TNF-alpha is an important component of the innate immune system and is produced upon activation of Toll-like receptor (TLR) pathways, we hypothesized that the mechanism associated with deficient TNF-alpha production in the lung involved altered TLR expression or a deficit in the TLR signaling cascade. We found decreased Toll-like receptor 1 (TLR1) and TLR4 surface expression in HIV-infected U1 monocytic cells compared to the uninfected parental U937 cell line and decreased TLR message in alveolar macrophages (AMs) from HIV-positive subjects. In addition, stimulation with TLR1/2 ligand (Pam(3)Cys) or TLR4 ligand (lipopolysaccharide) resulted in decreased intracellular phosphorylated extracellular signal-regulated kinase and subsequent decreased transcription and expression of TNF-alpha in U1 cells compared to U937 cells. AMs from HIV-positive subjects also showed decreased TNF-alpha production in response to these TLR2 and TLR4 ligands. We postulate that HIV infection alters expression of TLRs with subsequent changes in mitogen-activated protein kinase signaling and cytokine production that ultimately leads to deficiencies of innate immune responses that predispose HIV-positive subjects to infection.



Prior exposure to LPS both in vitro and in vivo can lead to desensitization of immune cells to subsequent challenge with LPS, a phenomenon that has been referred to as "endotoxin tolerance."

Induction of in vitro reprogramming by Toll-like receptor (TLR)2 and TLR4 agonists in murine macrophages: effects of TLR "homotolerance" versus "heterotolerance" on NF-kappa B signaling pathway components.

Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201, USA.

In this study, tolerance induction by preexposure of murine macrophages to Toll-like receptor (TLR)2 and TLR4 agonists was revisited, focusing on the major signaling components associated with NF-kappaB activation. Pretreatment of macrophages with a pure TLR4 agonist (protein-free Escherichia coli (Ec) LPS) or with TLR2 agonists (Porphyromonas gingivalis LPS or synthetic lipoprotein Pam3Cys) led to suppression of TNF-alpha secretion, IL-1R-associated kinase-1, and IkappaB kinase (IKK) kinase activities, c-jun N-terminal kinase, and extracellular signal-regulated kinase phosphorylation, and to suppression of NF-kappaB DNA binding and transactivation upon challenge with the same agonist (TLR4 or TLR2 "homotolerance," respectively). Despite inhibited NF-kappaB DNA binding, increased levels of nuclear NF-kappaB were detected in agonist-pretreated macrophages. For all the intermediate signaling elements, heterotolerance was weaker than TLR4 or TLR2 homotolerance with the exception of IKK kinase activity. IKK kinase activity was unperturbed in heterotolerance. TNF-alpha secretion was also suppressed in P. gingivalis LPS-pretreated, Ec LPS-challenged cells, but not vice versa, while Pam3Cys and Ec LPS did not induce a state of cross-tolerance at the level of TNF-alpha. Experiments designed to elucidate novel mechanisms of NF-kappaB inhibition in tolerized cells revealed the potential contribution of IkappaBepsilon and IkappaBxi inhibitory proteins and the necessity of TLR4 engagement for induction of tolerance to Toll receptor-IL-1R domain-containing adapter protein/MyD88-adapter-like-dependent gene expression. Collectively, these data demonstrate that induction of homotolerance affects a broader spectrum of signaling components than in heterotolerance, with selective modulation of specific elements within the NF-kappaB signaling pathway.


8)  Lipid-associated membrane proteins of Mycoplasma fermentans and M. penetrans activate human immunodeficiency virus long-terminal repeats through Toll-like receptors
Takashi Shimizu, Yutaka Kida, and Koichi Kuwano
Department of Bacteriology, Kurume University School of Medicine, Kurume, Japan
Immunology. 2004 September; 113(1): 121–129.
Mycoplasmas are known to enhance human immunodeficiency virus (HIV) replication, and mycoplasma-derived lipid extracts have been reported to activate nuclear factor-κB (NF-κB) through Toll-like receptors (TLRs). In this study, we examined the involvement of TLRs in the activation of HIV long-terminal repeats (LTR) by mycoplasma and their active components responsible for the TLR activation. Lipid-associated membrane proteins (LAMPs) from two species of mycoplasma (Mycoplasma fermentans and M. penetrans) that are associated with acquired immune-deficiency syndrome (AIDS), were found to activate HIV LTRs in a human monocytic cell line, THP-1. NF-κB deletion from the LTR resulted in inhibition of the activation. The LTR activation by M. fermentans LAMPs was inhibited by a dominant negative (DN) construct of TLR1 and TLR6, whereas HIV LTR activation by M. penetrans LAMPs was inhibited by DN TLR1, but not by DN TLR6. These results indicate that the activation of HIV LTRs by M. fermentans and M. penetrans LAMPs is dependent on NF-κB, and that the activation of HIV LTR by M. fermentans LAMPs is mediated through TLR1, TLR2 and TLR6. In contrast, the LTR activation by M. penetrans LAMPs is carried out through TLR1 and TLR2, but not TLR6. Subsequently, the active component of M. penetrans and M. fermentans LAMPs was purified by reverse-phase high-performance liquid chromatography (HPLC). Interestingly, the purified lipoprotein of M. penetrans LAMPs (LPMp) was able to activate NF-κB through TLR1 and TLR2. On the other hand, the activation of NF-κB by purified lipoprotein of M. fermentans LAMPs (LPMf) was mediated through TLR2 and TLR6, but not TLR1.
Keywords: HIV, lipoprotein, mycoplasma, Toll-like receptor


In mycoplasmas, acylated proteins are abundant cell-surface antigens, and many putative lipoprotein-encoding genes have been identified in the sequenced mycoplasma genomes.49,50 It is, at present, controversial as to whether or not mycoplasmas have triacylated lipoprotein. Chemically identified lipoproteins from M. fermentans,44M. hyorhinis,51M. salivarium46 and M. gallisepticum52 are not N-acylated, nor has an N-acyltransferase gene been found in M. pneumoniae,53M. genitalium54 or M. penetrans55 genomes. To date, the presence of proteins with N-acyltransferase activity has not been clearly established. However, the study on the ratio of N-amide and O-ester bonds in M. gallisepticum and M. mycoides may indicate the presence of diacylated and triacylated lipoproteins.56 The resistance to Edoman degradation of proteins from M. mycoides also indicates the presence of N-acylation.50 In this study, we found that the lipoprotein separated from M. penetrans induced NF-κB through TLR1 and TLR2. Triacylated lipoproteins, such as Pam3-CSK4, have been reported to be recognized by TLR1 and TLR2,43 whereas diacylated lipoproteins, such as MALP-2, have been shown to be recognized by TLR2 and TLR6.42 Interestingly, synthetically triacylated MALP-2, N-palamitoyl-MALP-2, was not recognized by TLR6.57 These findings may indicate the existence of triacylated lipoproteins in mycoplasma species.


9) BRUCELLA and Pam3Cys causing immune suppression:

Brucella abortus Inhibits Major Histocompatibility Complex Class II Expression and Antigen Processing through Interleukin-6 Secretion via Toll-Like Receptor 2[down-pointing small open triangle]

Infect Immun. 2008 January; 76(1): 250–262.

The strategies that allow Brucella abortus to survive inside macrophages for prolonged periods and to avoid the immunological surveillance of major histocompatibility complex class II (MHC-II)-restricted gamma interferon (IFN-γ)-producing CD4+ T lymphocytes are poorly understood. We report here that infection of THP-1 cells with B. abortus inhibited expression of MHC-II molecules and antigen (Ag) processing. Heat-killed B. abortus (HKBA) also induced both these phenomena, indicating the independence of bacterial viability and involvement of a structural component of the bacterium. Accordingly, outer membrane protein 19 (Omp19), a prototypical B. abortus lipoprotein, inhibited both MHC-II expression and Ag processing to the same extent as HKBA. Moreover, a synthetic lipohexapeptide that mimics the structure of the protein lipid moiety also inhibited MHC-II expression, indicating that any Brucella lipoprotein could down-modulate MHC-II expression and Ag processing. Inhibition of MHC-II expression and Ag processing by either HKBA or lipidated Omp19 (L-Omp19) depended on Toll-like receptor 2 and was mediated by interleukin-6. HKBA or L-Omp19 also inhibited MHC-II expression and Ag processing of human monocytes. In addition, exposure to the synthetic lipohexapeptide inhibited Ag-specific T-cell proliferation and IFN-γ production of peripheral blood mononuclear cells from Brucella-infected patients. Together, these results indicate that there is a mechanism by which B. abortus may prevent recognition by T cells to evade host immunity and establish a chronic infection.



The 19-kD antigen and protective immunity in a murine model of tuberculosis. 
Yeremeev VV, Lyadova IV, Nikonenko BV, Apt AS, Abou-Zeid C, Inwald J, Young DB.

"The 19-kD antigen is a cell wall-associated lipoprotein present in Mycobacterium tuberculosis and in bacille Calmette-Guérin (BCG) vaccine strains. Expression of the 19-kD antigen as a recombinant protein in two saprophytic mycobacteria-M. vaccae and M. smegmatis-resulted in abrogation of their ability to confer protection against M. tuberculosis in a murine challenge model, and in their ability to prime a DTH response to cross-reactive mycobacterial antigens. Induction of an immune response to the 19-kD antigen by an alternative approach of DNA vaccination had no effect on subsequent M. tuberculosis challenge. These results are consistent with a model in which the presence of the 19-kD protein has a detrimental effect on the efficacy of vaccination with live mycobacteria. Targeted inactivation of genes encoding selected antigens represents a potential route towards development of improved vaccine candidates."

Mycobacterium tuberculosis 19-kilodalton lipoprotein inhibits Mycobacterium smegmatis-induced cytokine production by human macrophages in vitro.

Post FA, Manca C, Neyrolles O, Ryffel B, Young DB, Kaplan G.

Vaccination of mice with Mycobacterium vaccae or M. smegmatis induces some protection against M. tuberculosis challenge. The 19-kDa lipoprotein of M. tuberculosis, expressed in M. vaccae or M. smegmatis (M. smeg19kDa), abrogates this protective immunity. To investigate the mechanism of this suppression of immunity, human monocyte-derived macrophages (MDM) were infected with M. smeg19kDa. Infection resulted in reduced production of tumor necrosis factor alpha (TNF-alpha) (P < 0.01), interleukin-12 (IL-12) (P < 0.05), IL-6 (P < 0.05), and IL-10 (P < 0.05), compared to infection with M. smegmatis vector (M. smegV). Infection with M. smeg19kDa and with M. smegV had no differential effect on expression of costimulatory molecules on MDM, nor did it affect the proliferation of presensitized T cells cocultured with infected MDM. When MDM were infected with M. smegmatis expressing mutated forms of the 19-kDa lipoprotein, including non-O-glycosylated (M. smeg19NOG), nonsecreted (M. smeg19NS), and nonacylated (M. smeg19NA) variants, the reduced production of TNF-alpha or IL-12 was not observed. When the purified 19-kDa lipoprotein was added directly to cultures of infected monocytes, there was little effect on either induction of cytokine production or its inhibition. Thus, the immunosuppressive effect is dependent on glycosylated and acylated 19-kDa lipoprotein present in the phagosome containing the mycobacterium. These results suggest that the diminished protection against challenge with M. tuberculosis seen in mice vaccinated with M. smegmatis expressing the 19-kDa lipoprotein is the result of reduced TNF-alpha and IL-12 production, possibly leading to reduced induction of T-cell activation."

  Infect Immun. 2003 Jun;71(6):3146-54. Related Articles, Links
The Mycobacterium tuberculosis recombinant 27-kilodalton lipoprotein induces a strong Th1-type immune response deleterious to protection.

Hovav AH, Mullerad J, Davidovitch L, Fishman Y, Bigi F, Cataldi A, Bercovier H.

Department of Clinical Microbiology, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.

Th1 immune response is essential in the protection against mycobacterial intracellular pathogens. Lipoproteins trigger both humoral and cellular immune responses and may be candidate protective antigens. We studied in BALB/c mice the immunogenicity and the protection offered by the recombinant 27-kDa Mycobacterium tuberculosis lipoprotein and the corresponding DNA vaccine. Immunization with the 27-kDa antigen resulted in high titers of immunoglobulin G1 (IgG1) and IgG2a with a typical Th1 profile and a strong delayed hypersensitivity response. A strong proliferation response was observed in splenocytes, and significant nitric oxide production and gamma interferon secretion but not interleukin 10 secretion were measured. Based on these criteria, the 27-kDa antigen induced a typical Th1-type immune response thought to be necessary for protection. Surprisingly, in 27-kDa-vaccinated mice (protein or DNA vaccines) challenged by M. tuberculosis H37Rv or BCG strains, there was a significant increase in the numbers of CFU in the spleen compared to that for control groups. Furthermore, the protection provided by BCG or other mycobacterial antigens was completely abolished once the 27-kDa antigen was added to the vaccine preparations. This study indicates that the 27-kDa antigen has an adverse effect on the protection afforded by recognized vaccines. We are currently studying how the 27-kDa antigen modulates the mouse immune response.