Myocardial disorders occur during influenza infection with a varying clinical severity that ranges from imperceptible symptoms to sudden unexpected death (SUD) [1, 2, 3, 4]. The association with sudden death is well-known and has been repeatedly described in animal studies [5, 6, 7], case reports [8, 9, 10], and review papers [11,12]. Most recently, compelling evidence for an association between influenza and SUD has been numerically quantified in a study by Onozuka and Hagihara  who reported on registry data for 481,516 out-of-hospital cardiac arrests from 47 prefectures of Japan during influenza seasons between 2005 and 2014.
Disappointingly, the causal mechanistic and molecular links between influenza epidemics and SUD remain unknown, However, it has to be annotated that influenza has been implicated as a potential trigger for autoimmune diseases such as diabetes [14,15], severe pulmonary inflammation in lupus-prone mice , thrombocytopenia , atherogenesis [17,18], narcolepsy [19, 20, 21, 22, 23, 24], brain autoimmunity , leukoencephalopathy , and neurological disorders and schizophrenia . Moreover, the reports [5, 6, 7, 8] that suggest a role of autoimmune processes in the development of influenza lesions in the myocardium are relevant in an immunological context.
Based on the abovementioned data, in this study, the possible immune link was analyzed by posing the following question: Do influenza antigens and human SUD-related proteins share peptides that might underlie autoimmune pathogenic cross-reactions? As a matter of fact, since 2010, this lab reported on an awesome peptide commonality between influenza hemagglutinin (HA) and the human proteome [27, 28, 29]. Such a peptide sharing might be potentially involved in neuropsychiatric disorders [28,29]. Instead, to the best of the current knowledge, no data have been reported on cross-reactivity as a possible autoimmune link between influenza infection and SUD. Using titin as a protein that, when altered, may associate with sudden death [30, 31, 32, 33, 34], this study specifically explored the peptide commonality between influenza viruses and titin, found viral vs human peptide overlaps that might represent a cross-reactive link to the pathological cardiac sequel, and investigated the structural basis of the potential cross-reactions.
Sequence analyses were conducted on human titin protein (UniProtKB ID: Q8WZ42, 34,350 amino acids [aa], that is described in detail at https://www.uniprot.org) [35, 36, 37] searching for peptide matches with influenza viruses.
The titin primary sequence was manipulated and analyzed as follows. The entire human protein was decomposed in silico to sets of overlapping n-mers (n from 10 to 7) offset by one residue, ie, MTTQAPTFTQ, TTQAPTFTQP, TQAPTFTQPL, and so on. Four libraries of unique 7-, 8-, 9-, and 10-mers were then created by removing duplicates. Next, for each n-mer in the libraries, the entire human proteome was searched for instances of the same n-mer. Any such occurrence was termed an overlap (or match). The titin n-mers were analyzed for matches in the UniProt/SwissProt database using Peptide Match Protein Information Resource (PIR) program (https://research.bioinformatics.udel.edu/peptidematch) . The resulting data sets were explored, and influenza viruses containing titin peptide matches were manually identified and annotated.
In addition, reference proteomes of influenza A virus, H3N2 subtype (tax ID: 385580), influenza B virus (tax ID: 518987), and influenza C virus (tax ID: 11553) were used to investigate peptide matching at the 5-mer level.
Immunological potential of shared peptides was analyzed using the Immune Epitope Database (IEDB; www.iedb.org) resource . IEDB offers experimental data characterizing antibody and T cell epitopes studied in human beings and other animal species. Epitopes involved in infectious disease, allergy, autoimmunity, and transplant are also included. This study considered only epitopes that had been experimentally validated as immunopositive in the human host.
PEP-FOLD3 program (http://bioserv.rpbs.univ-paris-diderot.fr/services/PEP-FOLD3) [39, 40, 41] was used to obtain three-dimensional (3D) conformational structures from linear aa sequences. Starting from a single linear peptide sequence, PEP-FOLD3 runs series of 100 tertiary structure simulations, with each simulation sampling a different region of the conformational space. Then, the program returns an archive of all the models generated. Once generated, models are clustered into 10 best models. In this study, the best model 1 was selected for each analyzed 18-mer peptide.
3 Results and discussion
3.1 Occurrence and conservativeness of a titin octapeptide in influenza A viruses
Sequence analyses of human titin protein vs influenza proteins at the 10-, 9-, 8-, and 7-mer levels show that the longest match is an octapeptide, namely AELLVLLE (Table 1).
Quantitative peptide sharing between human cardiac titin and influenza viruses at the 10-, 9-, 8-, and 7-mer levels
Focusing on the AELLVLLE octapeptide and analyzing the influenza viruses involved in the sharing, it was found that the octapeptide AELLVLLE is conserved among HAs from numerous influenza A viruses, mostly H1N1 subtype variants (Table 2), thus conflicting with the high mutation rate of influenza virus [42, 43, 44, 45]. To better evaluate AELLVLLE sequence conservativeness, Table 2 summarizes the viral aa sequence context of AELLVLLE, ie, the residues at the NH2 and COOH termini flanking the octapeptide (aa given in small letters in Table 2).
Distribution and conservativeness of the titin octapeptide AELLVLLE in influenza A virus HAs
|aa sequencea||Influenza A virus subtypes and variants|
|A/Puerto Rico/8/1934 H1N1|
|A/New Zealand:South Canterbury/35/2000 H1N1|
|A/Swine/New Jersey/11/1976 H1N1|
|A/Brevig Mission/1/1918 H1N1|
|vwtynAELLVLLEnertl||A/Russia:St. Petersburg/8/2006 H1N1|
On the whole, two unexpected data emerge from Tables 1 and 2. First, one out of the 34,343 titin octa-peptides occurs in the HA antigen from numerous influenza A virus subtypes and variants. This datum is unexpected since, neglecting aa frequency and protein length, the theoretical probability for two proteins to share one octapeptide approximates one out of 208, ie, the probability is 0.0000000000390625. It is an infinitesimal number that, in practice, is equal to zero.
The second unexpected datum is the conservativeness of the AELLVLLE sequence. Such a conservativeness is well documented in Table 2 by the fact that the short N and C termini flanking the conserved octa-peptide have a high level of aa variations, with only five invariant aa positions (aa are given in small letters and underlined in Table 2), in this way generating four different aa contexts (ie, 18-mer iwaynAELLVLLEnqktl, iwtynAELLVLLEnertl, lwaynAELLVLLEnqktl, and vwtynAELLVLLEnertl) for the conserved AELLVLLE sequence.
Moreover, Table 2 summarizes that the titin octapeptide is present in numerous influenza A subtypes, including a low pathogenic avian influenza A subtype such as H9N2 [46,47], but not in influenza B and C viruses or in other influenza A virus subtypes such as H3N2, a subtype that dominated recent influenza epidemics .
3.2 Occurrence and conservativeness of the titin octapeptide mimic AELLVALE in influenza A virus H3N2 subtype
To better define the peptide sharing with influenza A, B, and C viruses, sequence matching analyses were extended to AELLVLLE subsequences and the octapeptide was further dissected into 7-, 6-, and 5-mer peptides offset by one residue each other, ie, AELLV, ELLVL, LLVLL, and LVLLE. Then, each of the 7-, 6-, and 5-mer peptides was analyzed for occurrences in reference proteomes for influenza A H3N2 subtype, influenza B, and influenza C (Section 2).
It was found that no matching occurs in influenza B and C proteomes and only one titin pentamer (AELLV) is shared with the HA (UniProtKB: D1LNT4_I63A3) from influenza A virus, subtype H3N2 (tax ID: 385580). Of note, the HA pentapeptide AELLV is followed by the tripeptide “ALE”. Said otherwise, it was noticed that a sequence AELLVALE that mimics the titin AELLVLLE peptide (with a Leu substituted by an Ala, see the A underlined in the mimic sequence) is present in influenza A virus HA, subtype H3N2.
Hence, search for matching was extended to the mimic peptide AELLVALE. Results are shown in Table 3 that summarizes that the mimic AELLVALE characterizes influenza A HAs from nine different subtypes. Moreover, Table 3 summarizes that, at difference from the AELLVLLE octapeptide, the conserved peptide mimic AELLVALE is flanked by likewise highly conserved NH2 and COOH termini, ie, the 18-mer lwsynAELLVALEnqht is a conserved sequence among the different influenza A virus subtypes and variants as listed in Table 3.
Occurrences of peptide mimic AELLVALE in influenza A virus HAs, subtypes H3N2, H3N8, H4N2, H4N4, H4N5, H4N6, H4N8, H14N5, and H14N6
|aa sequencea||Influenza A virus subtype|
|Hong Kong/1/1968 H3N2|
|Hong Kong/5/1983 H3N2|
|Port Chalmers/1/1973 H3N2|
|Equine/New Market/1976 H3N8|
|Grey teal/Australia/2/1979 H4N4|
|Ruddy Turnstone/New Jersey/47/1985 H4N6|
3.3 Immunological potential of the AELLVLLE peptide and its mimic AELLVALE
Subsequently, exploration of IEDB (www.iedb.org)  showed that the titin AELLVLLE peptide and its mimic AELLVALE have an immunological potential. Indeed, the octapeptides AELLVLLE and AELLVALE are present in influenza HA epitopes experimentally validated and cataloged as immunopositive in the human host [49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61] (Table 4).
Immunopositive influenza virus HA epitope sequences containing the octapeptide AELLVLLE or its mimic AELLVALE
|129015||iwtynAELLVLLEnert||51, 55, 56|
3.4 Viral sequence contexts of the two octapeptide determinants AELLVLLE and AELLVALE: the “same peptide–different conformational structures” issue
To understand how the two determinants AELLVLLE and AELLVALE might be involved in potential cross-reactive responses between the human cardiac titin protein and influenza A HA antigens, the role of the short 5 aa regions flanking the NH2 and COOH termini was investigated. Indeed, a main point that emerges by comparing Tables 2 and 3 is that the determinant AELLVLLE is flanked by aa sequences that vary (Table 2), whereas the peptide mimic AELLVALE lies in a highly conserved aa frame (Table 3).
This point might be of relevance in specifying the immunoreactivity of the two octapeptide immunode-terminants. In fact, already in 1984, Kabsch and Sander [62,63] demonstrated that the structure of a short peptide within a protein strongly depends on the sequence context. That is to say that the peptide interactions with other parts of a protein dictate the peptide conformation so that identical peptide segments can assume different conformations in different proteins. Immunologically, the “same peptide–different conformational structures” issue is of utmost importance since it can underlie a humoral immune response formed by a constellation of antibodies with different specificities to the many conformers of a peptide [64, 65, 66].
Hence, the 3D structures of AELLVLLE and its mimic AELLVALE were analyzed as a function of the aa sequence context, ie, of the NH2 and COOH termini. Specifically, molecular modeling was applied to six 18-mer peptides:
- - 1) estcaAELLVLLEdtdmt (ie, the 18-mer sequence present in the titin protein),
- - 2) iwaynAELLVLLEnqktl
- - 3) iwtynAELLVLLEnertl
- - 4) lwaynAELLVLLEnqktl
- - 5) vwtynAELLVLLEnertl (ie, the 18-mer sequences as described in Table 2)
- - 6) lwsynAELLVALEnqhti (ie, the 18-mer sequence as described in Table 3)
Results are illustrated in Figure 1 that shows the different structural conformations of the two octapeptide determinants in the different aa frames listed earlier and obtained by using PEP-FOLD3 program [39, 40, 41]. For simplicity, Figure 1 only mentions subtype H3N2 out of the nine HN subtypes characterized by the 18-mer lwsynAELLVALEnqhti sequence.
3.5 Context-dependent conformational structures of determinants AELLVLLE and AELLVALE
Figure 1 shows that only viral sequences corresponding to structures 5 and 6 are similar to the titin structure 1, thereby owning the proper 3D configuration to elicit immune responses able to cross-react with the human cardiac titin protein.
In fact, in line with the Kabsch and Sander’s “same sequence–different structure” principle [49,50], Figure 1 shows that the four varying frames as described in Table 2 generate four different AELLVLLE conformers (Figure 1, structures 2, 3, 4, and 5). Among them, structure 5 is similar in shape and charge to the AELLVLLE conformation defined by the human titin context (Figure 1, structure 1). Instead, structures 2, 3, and 4 would be excluded from participating to possible cross-reactions with titin because of the hydrophobic 3D surface characterized by L8, L11, and L12 residues in structures 2 and 3, and possibly by the V10 smoothed spike in structure 4. Instead, the physicochemical features of structures 1 and 5 as given by the succession of A6, L9, and E13 residues are also found in structure 6, where the mimic AELLVALE allocates in the unvarying 18-mer sequence lwsynAELLVALEnqhti present in influenza A virus H3N2 and other eight influenza A subtypes (Table 3).
In short, only determinant conformers 1, 5, and 6 are structurally similar so as to represent the main target for possible cross-reactions between the human cardiac titin protein and influenza HA antigen. This datum merits attention especially in analyzing the recent 2018 influenza epidemic that essentially consisted of A(H1N1)pdm09 and A(H3N2) infections  and was heavily burdened by SUD cases . Actually, influenza A(H1N1)pdm09 HA sequenced in 400 samples collected in the period January–May 2018 (Table S1) was marked by the presence of the 18-mer iwtynAELLVLLEnertl corresponding to structure 3 that is dissimilar in shape and charge from the titin structure 1 (Figure 1). This would exclude a possible role of influenza A(H1N1) pdm09 infection in inducing autoimmune cross-reactions with the human cardiac titin protein. Instead, a potential cross-reactive role is likely for influenza A virus H3N2 that hosts the 18-mer lwsynAELLVALEnqhti sequence structurally corresponding to a conformer (Figure 1, structure 6) that is similar to that of titin (Figure 1, structure 1).
List of sequence entries of influenza A(H1N1)pdm09 HA derived from 400 samples collected in the period January–May 2018. Data obtained from NCBI using the keywords “influenza A(H1N1)pdm09 HA 2018 complete sequence”
|MH443420.1 MH443428.1 MH443436.1 MH443444.1 MH443446.1 MH443492.1 MH443500.1 MH443571.1 MH443588.1|
|MH443613.1 MH443628.1 MH446409.1 MH446416.1 MH446422.1 MH446429.1 MH446436.1 MH446441.1 MH446447.1|
|MH446454.1 MH446461.1 MH446467.1 MH446474.1 MH446479.1 MH446486.1 MH446493.1 MH446500.1 MH446508.1|
|MH446517.1 MH446524.1 MH446529.1 MH446540.1 MH446548.1 MH446555.1 MH446564.1 MH446572.1 MH446580.1|
|MH446588.1 MH446596.1 MH446604.1 MH446612.1 MH446620.1 MH446628.1 MH446636.1 MH446645.1 MH446653.1|
|MH446660.1 MH446668.1 MH446677.1 MH446686.1 MH446692.1 MH446700.1 MH446708.1 MH446716.1 MH446725.1|
|MH446732.1 MH446740.1 MH446748.1 MH446756.1 MH446764.1 MH446772.1 MH446780.1 MH446788.1 MH446796.1|
|MH446804.1 MH446812.1 MH446820.1 MH446828.1 MH446838.1 MH446844.1 MH446852.1 MH446860.1 MH446868.1|
|MH446874.1 MH446884.1 MH446892.1 MH446900.1 MH446908.1 MH446916.1 MH446924.1 MH446932.1 MH446940.1|
|MH446948.1 MH446954.1 MH446964.1 MH446972.1 MH359761.1 MH359768.1 MH359773.1 MH359779.1 MH359782.1|
|MH359789.1 MH359800.1 MH359806.1 MH359814.1 MH359822.1 MH359831.1 MH359838.1 MH359846.1 MH359854.1|
|MH359862.1 MH359870.1 MH359878.1 MH359886.1 MH359894.1 MH359900.1 MH359910.1 MH359918.1 MH359923.1|
|MH359935.1 MH359942.1 MH359950.1 MH359958.1 MH359966.1 MH359974.1 MH359982.1 MH359990.1 MH359998.1|
|MH360007.1 MH360014.1 MH360024.1 MH360030.1 MH360038.1 MH360046.1 MH360055.1 MH360062.1 MH360070.1|
|MH360078.1 MH360086.1 MH360094.1 MH360102.1 MH360111.1 MH360121.1 MH360126.1 MH360134.1 MH360142.1|
|MH360150.1 MH360158.1 MH360166.1 MH360174.1 MH360182.1 MH360190.1 MH360198.1 MH360206.1 MH360214.1|
|MH360222.1 MH305586.1 MH305593.1 MH305600.1 MH305607.1 MH305613.1 MH305620.1 MH305628.1 MH305636.1|
|MH305644.1 MH305652.1 MH305660.1 MH305668.1 MH305676.1 MH305684.1 MH305692.1 MH305700.1 MH305708.1|
|MH305716.1 MH305724.1 MH305732.1 MH305740.1 MH305748.1 MH305756.1 MH305764.1 MH305772.1 MH305780.1|
|MH305788.1 MH305796.1 MH305807.1 MH305812.1 MH305820.1 MH305828.1 MH305836.1 MH305843.1 MH305849.1|
|MH305863.1 MH305868.1 MH305876.1 MH305884.1 MH305892.1 MH305900.1 MH305908.1 MH305916.1 MH305927.1|
|MH305932.1 MH305940.1 MH305948.1 MH305956.1 MH305964.1 MH305972.1 MH305980.1 MH305988.1 MH305999.1|
|MH306004.1 MH306012.1 MH306023.1 MH306028.1 MH306035.1 MH306044.1 MH306052.1 MH306060.1 MH306068.1|
|MH306076.1 MH306084.1 MH245831.1 MH245838.1 MH245845.1 MH245852.1 MH245859.1 MH245866.1 MH245873.1|
|MH245880.1 MH245887.1 MH245894.1 MH245901.1 MH245909.1 MH245917.1 MH245925.1 MH245930.1 MH245941.1|
|MH245949.1 MH245957.1 MH245965.1 MH245973.1 MH245981.1 MH245989.1 MH245997.1 MH246005.1 MH246013.1|
|MH246021.1 MH246029.1 MH246037.1 MH246045.1 MH246053.1 MH246061.1 MH246069.1 MH246077.1 MH246085.1|
|MH246101.1 MH246109.1 MH246117.1 MH246125.1 MH246133.1 MH246141.1 MH246149.1 MH246157.1 MH246165.1|
|MH246173.1 MH246181.1 MH246189.1 MH246197.1 MH246205.1 MH233583.1 MH233589.1 MH233596.1 MH233604.1|
|MH233612.1 MH233620.1 MH233628.1 MH233636.1 MH233644.1 MH233652.1 MH233660.1 MH233668.1 MH233676.1|
|MH233684.1 MH183265.1 MH183273.1 MH183281.1 MH183398.1 MH183404.1 MH183416.1 MH183418.1 MH183425.1|
|MH183432.1 MH183439.1 MH183446.1 MH183453.1 MH183461.1 MH183469.1 MH183477.1 MH183489.1 MH183493.1|
|MH183498.1 MH183509.1 MH183518.1 MH183525.1 MH183533.1 MH183541.1 MH183546.1 MH183557.1 MH183565.1|
|MH183573.1 MH183578.1 MH183589.1 MH183597.1 MH183605.1 MH183613.1 MH183621.1 MH183629.1 MH183637.1|
|MH183645.1 MH183653.1 MH183661.1 MH183669.1 MH183677.1 MH183685.1 MH183693.1 MH183702.1 MH183709.1|
|MH183717.1 MH183725.1 MH183733.1 MH183741.1 MH183749.1 MH183757.1 MH183765.1 MH183777.1 MH183781.1|
|MH183789.1 MH183797.1 MH183805.1 MH183813.1 MH183821.1 MH183829.1 MH183837.1 MH183845.1 MH183853.1|
|MH183861.1 MH183869.1 MH183877.1 MH183885.1 MH183890.1 MH183901.1 MH183908.1 MH183917.1 MH183925.1|
|MH183934.1 MH183938.1 MH183949.1 MH183957.1 MH183965.1 MH183973.1 MH183981.1 MH183990.1 MH183997.1|
|MH184005.1 MH184013.1 MH184021.1 MH184029.1 MH184036.1 MH125461.1 MH125467.1 MH125470.1 MH125479.1|
|MH125486.1 MH125492.1 MH125498.1 MH125505.1 MH125512.1 MH125525.1 MH125539.1 MH125546.1 MH125553.1|
|MH125560.1 MH125567.1 MH125574.1 MH125581.1 MH125584.1 MH125595.1 MH125596.1 MH125597.1 MH125602.1|
|MH125610.1 MH125618.1 MH125626.1 MH125634.1 MH125642.1 MH125650.1 MH125658.1 MH125667.1 MH125674.1|
|MH125681.1 MH125690.1 MH125697.1 MH125706.1 MH125714.1 MH125723.1 MH125730.1 MH125738.1 MH125745.1|
|MH125754.1 MH125760.1 MH125768.1 MH125777.1|
Immunological phenomena are complex, and it is well-known that the generation of immune responses (immunogenicity) and antigen recognition by antibodies (antigenicity) are influenced by a plethora of cellular and humoral factors (ie, T cells and cytokines) under the constraint of physicochemical conditions such as pH, antigen concentration, ionic strength, hydrophilicity/hydrophobicity, and epitope accessibility . Hence, the structural data graphically exposed in this study cannot be assumed as absolute certainty but, rather, are preliminary to further research aimed at mathematically defining epitope structures by the analysis of, for example, root-mean-square deviation of atomic positions and, as well, at determining the stability of the various peptide conformations. In addition, studies of biochemical factors such as glycosylation and proteolysis have to be conducted for taking into consideration the structural conformer as an optimal epitope .
Of cogent importance for defining future research, it has also to be noted that the structures selected by using PEP-FOLD3 [39, 40, 41] as shown in Figure 1 are not static and do not provide a definitive representation of the 18-mer sequences since each sequence actually “resonates” among multiple dynamic status, the stability of which is dictated by the stereochemical properties of amide linkages, double bonds, SH groups, et alia. In the case in point, such a resonance among multiple dynamic configurations is enhanced by the presence of aromatic aa (W, Y) in the sequence contexts shown in Figure 1.
In addition, it deserves notice the fact that the present study is restricted to human cardiac titin, a protein essential for both mechanical and signaling functions of the heart [30, 31, 32, 33 34, 71]. De facto, the number of human proteins crucial for cardiac functions is highest [72,73] and warrants extensive further analyses. In this regard, the data offered in this study do no more than to indicate the vastity of the potential cross-reactivity network connecting influenza infection and cardiovascular diseases.
Given these caveats, the conclusion of this study is that the data discussed might help our understanding of what has been and is still considered as a mysterious enigmatic phenomenon, ie, the influenza-associated pathogenicity [74,75,76].
Finally, from a biochemical point of view, it is important to annotate that the unexpected and apparently unexplainable viral vs human peptide matching most possibly derives from the central role played by viruses in the evolutionary origin of the eukaryotic nucleus, as described by the viral eukaryogenesis hypothesis [77, 78, 79].
This research received no specific grants from any funding agency in public, commercial, or not-for-profit sectors.
Ukimura A. Ooi Y. Kanzaki Y. Inomata T. Izumi T. A national survey on myocarditis associated with influenza H1N1pdm2009 in the pandemic and postpandemic season in Japan J. Infect. Chemother. 2013 19(3) 426-431.
Estabragh Z.R. Mamas M.A. The cardiovascular manifestations of influenza: a systematic review Int. J. Cardiol. 2013 167(6) 2397-2403.
Mamas M.A. Fraser D. Neyses L. Cardiovascular manifestations associated with influenza virus infection Int. J. Cardiol. 2008 130(3) 304-309.
Ukimura A. Satomi H. Ooi Y. Kanzaki Y. Myocarditis associated with Influenza A H1N1pdm2009 Influenza Res. Treat. 2012 2012 351979.
Solov’ev A.V.D. Gutman N.R. Khesin Y.E. Kognovitskaya A.I. Experimental myocarditis induced in albino mice by influenza virus Bull. Exp. Biol. Med. 1973 76 1359.
Sakamoto M. Suzuki F. Arai S. Takishima T. Ishida N. Experimental myocarditis induced in mice by infection with influenza A2 virus Microbiol. Immunol. 1981 25(2) 173-181.
Kotaka M. Kitaura Y. Deguchi H. Kawamura K. Experimental influenza A virus myocarditis in mice. Light and electron microscopic virologic and hemodynamic study Am. J. Pathol. 1990 136(2) 409-419.
Engblom E. Ekfors T.O. Meurman O.H. Toivanen A. Nikoskelainen J. Fatal influenza A myocarditis with isolation of virus from the myocardium Acta Med. Scand. 1983 213(1) 75-78.
Landi K.K. Coleman A.T. Sudden death in toddlers caused by influenza B infection: a report of two cases and a review of the literature J. Forensic Sci. 2008 53(1) 213-215.
Lobo M.L. Taguchi Â Gaspar H.A. Ferranti J.F. de Carvalho W.B. Delgado A.F. Fulminant myocarditis associated with the H1N1 influenza virus: case report and literature review Rev. Bras. Ter. Intensiva. 2014 26(3) 321-326.
Prandoni S. Sudden and fulminant deaths of healthy children in Italy during the 2010-11 and 2011-12 seasons: results of an online study J. Public Health Res. 2012 1(2) 184-191.
Puliyel J. Sathyamala C. Infanrix hexa and sudden death: a review of the periodic safety update reports submitted to the European Medicines Agency Indian J. Med. Ethics 2018 3(1) 43-47.
Onozuka D. Hagihara A. Extreme influenza epidemics and out-of-hospital cardiac arrest Int. J. Cardiol. 2018 263 158-162.
Yasuda H. Nagata M. Moriyama H. Kobayashi H. Akisaki T. Ueda H. et al. Development of fulminant Type 1 diabetes with thrombocytopenia after influenza vaccination: a case report Diabet. Med. 2012 29(1) 88-89.
Capua I. Mercalli A. Romero-Tejeda A. Pizzuto M.S. Kasloff S. Sordi V. et al. Study of 2009 H1N1 pandemic influenza virus as a possible causative agent of diabetes J. Clin. Endocrinol. Metab. 2018 103(12) 4343-4356..
Slight-Webb S.R. Bagavant H. Crowe S.R. James J.A. Influenza A (H1N1) virus infection triggers severe pulmonary inflammation in lupus-prone mice following viral clearance J. Autoimmun. 2015 57 66-76.
Gurevich V.S. Pleskov V.M. Levaya M.V. Autoimmune nature of influenza atherogenicity Ann. N. Y. Acad. Sci. 2005 1050 410-416.
Gurevich V.S. Influenza autoimmunity and atherogenesis Autoimmun. Rev. 2005 4(2) 101-105.
Dye T.J. Gurbani N. Simakajornboon N. Epidemiology and pathophysiology of childhood narcolepsy Paediatr. Respir. Rev. 2018 25 14-18.
Bonvalet M. Ollila H.M. Ambati A. Mignot E. Autoimmunity in narcolepsy Curr. Opin. Pulm. Med. 2017 23(6) 522-529.
Tesoriero C. Codita A. Zhang M.D. Cherninsky A. Karlsson H. Grassi-Zucconi G. et al. H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep-wake regulatory neurons in mice Proc. Natl. Acad. Sci. USA 2016 113(3) E368-E377.
- Export Citation
Tesoriero C., Codita A., Zhang M.D., Cherninsky A., Karlsson H., Grassi-Zucconi G., et al., H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep-wake regulatory neurons in mice, Proc. Natl. Acad. Sci. USA, 2016, 113(3), E368-E377.)| false 10.1073/pnas.1521463112
Saariaho A.H. Vuorela A. Freitag T.L. Pizza F. Plazzi G. Partinen M. et al. Autoantibodies against ganglioside GM3 are associated with narcolepsy-cataplexy developing after Pandemrix vaccination against 2009 pandemic H1N1 type influenza virus J. Autoimmun. 2015 63 68-75.
- Export Citation
Saariaho A.H., Vuorela A., Freitag T.L., Pizza F., Plazzi G., Partinen M., et al., Autoantibodies against ganglioside GM3 are associated with narcolepsy-cataplexy developing after Pandemrix vaccination against 2009 pandemic H1N1 type influenza virus, J. Autoimmun., 2015, 63, 68-75.)| false 10.1016/j.jaut.2015.07.006 26227560
Ahmed S.S. Schur P.H. MacDonald N.E. Steinman L. Narcolepsy 2009 A(H1N1) pandemic influenza and pandemic influenza vaccinations: what is known and unknown about the neurological disorder the role for autoimmunity and vaccine adjuvants J. Autoimmun. 2014 50 1-11.
- Export Citation
Ahmed S.S., Schur P.H., MacDonald N.E., Steinman L., Narcolepsy, 2009 A(H1N1) pandemic influenza, and pandemic influenza vaccinations: what is known and unknown about the neurological disorder, the role for autoimmunity, and vaccine adjuvants, J. Autoimmun., 2014, 50, 1-11.)| false 10.1016/j.jaut.2014.01.033 24559657
Kornum B.R. Faraco J. Mignot E. Narcolepsy with hypocretin/orexin deficiency infections and autoimmunity of the brain Curr. Opin. Neurobiol. 2011 21(6) 897-903.
Jeganathan N. Fox M. Schneider J. Gurka D. Bleck T. Acute hemorrhagic leukoencephalopathy associated with influenza A (H1N1) virus Neurocrit. Care. 2013 19(2) 218-221.
Khandaker G.M. Zimbron J. Lewis G. Jones P.B. Prenatal maternal infection neurodevelopment and adult schizophrenia: a systematic review of population-based studies Psychol. Med. 2013 43(2) 239-257.
Kanduc D. Describing the hexapeptide identity platform between the influenza A H5N1 and Homo sapiens proteomes Biologics. 2010 4 245-261.
Lucchese G. Capone G. Kanduc D. Peptide sharing between influenza A H1N1 hemagglutinin and human axon guidance proteins Schizophr. Bull. 2014 40(2) 362-375.
Lucchese G. Capone G. Kanduc D. H1N1 versus H5N1 hemagglutinins A possible differential immunologic impact on neurodevelopment Neurol. Psychiatry Brain Res. 2015 21(1) 39-50.
Anderson B.R. Bogomolovas J. Labeit S. Granzier H. Single molecule force spectroscopy on Titin implicates immunoglobulin domain stability as a cardiac disease mechanism J. Biol. Chem. 2013 288(8) 5303-5315.
Brun F. Barnes C.V. Sinagra G. Slavov D. Barbati G. Zhu X. et al. Titin and desmosomal genes in the natural history of arrhythmogenic right ventricular cardiomyopathy J. Med. Genet. 2014 51(10) 669-676.
Campuzano O. Sanchez-Molero O. Mademont-Soler I. Riuró H. Allegue C. Coll M. et al. Rare Titin (TTN) variants in diseases associated with sudden cardiac death Int. J. Mol. Sci. 2015 16(10) 25773-25787.
Pérez-Serra A. Toro R. Sarquella-Brugada G. de Gonzalo-Calvo D. Cesar S. Carro E. et al. Genetic basis of dilated cardiomyopathy Int. J. Cardiol. 2016 224 461-472.
Suktitipat B. Sathirareuangchai S. Roothumnong E. Thongnoppakhun W. Wangkiratikant P. Vorasan N. et al. Molecular investigation by whole exome sequencing revealed a high proportion of pathogenic variants among Thai victims of sudden unexpected death syndrome PLoS One 2017 12(7) e0180056.
- Export Citation
Suktitipat B., Sathirareuangchai S., Roothumnong E., Thongnoppakhun W., Wangkiratikant P., Vorasan N., et al., Molecular investigation by whole exome sequencing revealed a high proportion of pathogenic variants among Thai victims of sudden unexpected death syndrome, PLoS One, 2017, 12(7), e0180056.)| false 28704380 10.1371/journal.pone.0180056
Chen C. Li Z. Huang H. Suzek B.E. Wu C.H. UniProt Consortium. A fast Peptide Match service for UniProt knowledgebase Bioinformatics 2013 29(21) 2808-2809.
Vita R. Overton J.A. Greenbaum J.A. Ponomarenko J. Clark J.D. Cantrell J.R. et al. The immune epitope database (IEDB) 3.0 Nucleic Acids Res. 2015 43(Database issue) D405-D412.
Shen Y. Maupetit J. Derreumaux P. Tufféry P. Improved PEP-FOLD approach for peptide and miniprotein structure prediction J. Chem. Theor. Comput. 2014 10(10) 4745-4758.
Lamiable A. Thevenet P. Tufféry P. A critical assessment of hidden Markov model sub-optimal sampling strategies applied to the generation of peptide 3D models J. Comput. Chem. 2016 37(21) 2006-2016.
Lamiable A. Thévenet P. Rey J. Vavrusa M. Derreumaux P. Tufféry P. PEP-FOLD3 faster de novo structure prediction for linear peptides in sol.ution and in complex Nucleic Acids Res. 2016 44(W1) W449-W454.
Shao W. Li X. Goraya M.U. Wang S. Chen J.L. Evolution of Influenza A virus by mutation and re-assortment Int. J. Mol. Sci. 2017 18(8) ii:E1650.
Reperant L.A. Grenfell B.T. Osterhaus A.D. Quantifying the risk of pandemic influenza virus evolution by mutation and re-assortment Vaccine 2015 33(49) 6955-6966.
Peng J. Yang H. Jiang H. Lin Y.X. Lu C.D. Xu Y.W. et al. The origin of novel avian influenza A (H7N9) and mutation dynamics for its human-to-human transmissible capacity PLoS One 2014 9 e93094.
García M. Suarez D.L. Crawford J.M. Latimer J.W. Slemons R.D. Swayne D.E. et al. Evolution of H5 subtype avian influenza A viruses in North America Virus Res. 1997 51 115-124.
Ge F.F. Zhou J.P. Liu J. Wang J. Zhang W.Y. Sheng L.P. et al. Genetic evolution of H9 subtype influenza viruses from live poultry markets i.n Shanghai China J. Clin. Microbiol. 2009 47 3294-3300.
Garten R. Blanton L. Elal A.I.A. Alabi N. Barnes J. Biggerstaff M. et al. Update: influenza activity in the United States during the 2017-18 season and composition of the 2018-19 influenza vaccine MMWR Morb. Mortal. Wkly. Rep. 2018 67 634-642.
- Export Citation
Garten R., Blanton L., Elal A.I.A., Alabi N., Barnes J., Biggerstaff M., et al., Update: influenza activity in the United States during the 2017-18 season and composition of the 2018-19 influenza vaccine, MMWR Morb. Mortal. Wkly. Rep., 2018, 67, 634-642.)| false 10.15585/mmwr.mm6722a4 29879098
Gelder C.M. Welsh K.I. Faith A. Lamb J.R. Askonas B.A. Human CD4+ T-cell repertoire of responses to influenza A virus hemagglutinin after recent natural infection J. Virol. 1995 69(12) 7497-7506.
Gelder C. Davenport M. Barnardo M. Bourne T. Lamb J. Askonas B. et al. Six unrelated HLA-DR-matched adults recognize identical CD4+ T cell epitopes from influenza A haemagglutinin that are not simply peptides with high HLA-DR binding affinities Int. Immunol. 1998 10(2) 211-222.
- Export Citation
Gelder C., Davenport M., Barnardo M., Bourne T., Lamb J., Askonas B., et al., Six unrelated HLA-DR-matched adults recognize identical CD4+ T cell epitopes from influenza A haemagglutinin that are not simply peptides with high HLA-DR binding affinities, Int. Immunol., 1998, 10(2), 211-222.)| false 10.1093/intimm/10.2.211 9533449
Richards K.A. Chaves F.A. Sant A.J. The memory phase of the CD4 T-cell response to influenza virus infection maintains its diverse antigen specificity Immunology 2011 133(2) 246-256.
Schanen B.C. De Groot A.S. Moise L. Ardito M. McClaine E. Martin W. et al. Coupling sensitive in vitro and in silico techniques to assess cross-reactive CD4(+) T cells against the swine-origin H1N1 influenza virus Vaccine 2011 29(17) 3299-3309.
- Export Citation
Schanen B.C., De Groot A.S., Moise L., Ardito M., McClaine E., Martin W., et al., Coupling sensitive in vitro and in silico techniques to assess cross-reactive CD4(+) T cells against the swine-origin H1N1 influenza virus, Vaccine, 2011, 29(17), 3299-3309.)| false 10.1016/j.vaccine.2011.02.019 21349362
Richards K.A. Chaves F.A. Sant A.J. Infection of HLA-DR1 transgenic mice with a human isolate of influenza a virus (H1N1) primes a diverse CD4 T-cell repertoire that includes CD4 T cells with heterosubtypic cross-reactivity to avian (H5N1) influenza virus J. Virol 2009 83(13) 6566-6577.
- Export Citation
Richards K.A., Chaves F.A., Sant A.J., Infection of HLA-DR1 transgenic mice with a human isolate of influenza a virus (H1N1) primes a diverse CD4 T-cell repertoire that includes CD4 T cells with heterosubtypic cross-reactivity to avian (H5N1) influenza virus, J. Virol, 2009, 83(13), 6566-6577.)| false 10.1128/JVI.00302-09 19386707
Richards K.A. Chaves F.A. Krafcik F.R. Topham D.J. Lazarski C.A. Sant A.J. Direct ex vivo analyses of HLA-DR1 transgenic mice reveal an exceptionally broad pattern of immunodominance in the primary HLA-DR1-restricted CD4 T-cell response to influenza virus hemagglutinin J. Virol 2007 81(14) 7608-7619.
- Export Citation
Richards K.A., Chaves F.A., Krafcik F.R., Topham D.J., Lazarski C.A., Sant A.J., Direct ex vivo analyses of HLA-DR1 transgenic mice reveal an exceptionally broad pattern of immunodominance in the primary HLA-DR1-restricted CD4 T-cell response to influenza virus hemagglutinin, J. Virol, 2007, 81(14), 7608-7619.)| false 10.1128/JVI.02834-06 17507491
Chaves F.A. Lee A.H. Nayak J.L. Richards K.A. Sant A.J. The utility and limitations of current Web-available algorithms to predict peptides recognized by CD4 T cells in response to pathogen infection J. Immunol. 2012 188(9) 4235-4248.
- Export Citation
Chaves F.A., Lee A.H., Nayak J.L., Richards K.A., Sant A.J., The utility and limitations of current Web-available algorithms to predict peptides recognized by CD4 T cells in response to pathogen infection, J. Immunol., 2012, 188(9), 4235-4248.)| false 10.4049/jimmunol.1103640 22467652
Babon J.A. Cruz J. Orphin L. Pazoles P. Co M.D. Ennis F.A. et al. Genome-wide screening of human T-cell epitopes in influenza A virus reveals a broad spectrum of CD4(+) T-cell responses to internal proteins hemagglutinins and neuraminidases Hum. Immunol. 2009 70(9) 711-721.
- Export Citation
Babon J.A., Cruz J., Orphin L., Pazoles P., Co M.D., Ennis F.A., et al., Genome-wide screening of human T-cell epitopes in influenza A virus reveals a broad spectrum of CD4(+) T-cell responses to internal proteins, hemagglutinins, and neuraminidases, Hum. Immunol., 2009, 70(9), 711-721.)| false 10.1016/j.humimm.2009.06.004 19524006
Duvvuri V.R. Duvvuri B. Jamnik V. Gubbay J.B. Wu J. Wu G.E. T cell memory to evolutionarily conserved and shared hemagglutinin epitopes of H1N1 viruses: a pilot scale study BMC Infect. Dis. 2013 13 204.
Zhao R. Cui S. Guo L. Wu C. Gonzalez R. Paranhos-Baccalà G. et al. Identification of a highly conserved H1 subtype-specific epitope with diagnostic potential in the hemagglutinin protein of influenza A virus PLoS One 2011 6(8) e23374.
- Export Citation
Zhao R., Cui S., Guo L., Wu C., Gonzalez R., Paranhos-Baccalà G., et al., Identification of a highly conserved H1 subtype-specific epitope with diagnostic potential in the hemagglutinin protein of influenza A virus, PLoS One, 2011, 6(8), e23374.)| false 21886787 10.1371/journal.pone.0023374
Yang J. James E. Gates T.J. DeLong J.H. LaFond R.E. Malhotra U. et al. CD4+ T cells recognize unique and conserved 2009 H1N1 influenza hemagglutinin epitopes after natural infection and vaccination Int. Immunol. 2013 25(8) 447-457.
Moise L. Tassone R. Latimer H. Terry F. Levitz L. Haran J.P. et al. Immunization with cross-conserved H1N1 influenza CD4+ T-cell epitopes lowers viral burden in HLA DR3 transgenic mice Hum. Vaccin. Immunother. 2013 9(10) 2060-2068.
- Export Citation
Moise L., Tassone R., Latimer H., Terry F., Levitz L., Haran J.P., et al., Immunization with cross-conserved H1N1 influenza CD4+ T-cell epitopes lowers viral burden in HLA DR3 transgenic mice, Hum. Vaccin. Immunother., 2013, 9(10), 2060-2068.)| false 10.4161/hv.26511 24045788
Klausberger M. Tscheliessnig R. Neff S. Nachbagauer R. Wohlbold T.J. Wilde M. et al. Globular head-displayed conserved influenza H1 hemagglutinin stalk epitopes confer protection against heterologous H1N1 virus PLoS One 2016 11(4) e0153579.
- Export Citation
Klausberger M., Tscheliessnig R., Neff S., Nachbagauer R., Wohlbold T.J., Wilde M., et al., Globular head-displayed conserved influenza H1 hemagglutinin stalk epitopes confer protection against heterologous H1N1 virus, PLoS One, 2016, 11(4), e0153579.)| false 10.1371/journal.pone.0153579 27088239
Kabsch W. Sander C. On the use of sequence homologies to predict protein structure: identical pentapeptides can have completely different conformations Proc. Natl. Acad. Sci. USA 1984 81(4) 1075-1078.
Niman H.L. Houghten R.A. Walker L.E. Reisfeld R.A. Wilson I.A. Hogle J.M. et al. Generation of protein-reactive antibodies by short peptides is an event of high frequency: implications for the structural basis of immune recognition Proc. Natl. Acad. Sci. USA 1983 80(16) 4949-4953.
- Export Citation
Niman H.L., Houghten R.A., Walker L.E., Reisfeld R.A., Wilson I.A., Hogle J.M., et al., Generation of protein-reactive antibodies by short peptides is an event of high frequency: implications for the structural basis of immune recognition, Proc. Natl. Acad. Sci. USA, 1983, 80(16), 4949-4953.)| false 10.1073/pnas.80.16.4949
Wilson I.A. Haft D.H. Getzoff E.D. Tainer J.A. Lerner R.A. Brenner S. Identical short peptide sequences in unrelated proteins can have different conformations: a testing ground for theories of immune recognition Proc. Natl. Acad. Sci. USA 1985 82(16) 5255-5259.
- Export Citation
Wilson I.A., Haft D.H., Getzoff E.D., Tainer J.A., Lerner R.A., Brenner S., Identical short peptide sequences in unrelated proteins can have different conformations: a testing ground for theories of immune recognition, Proc. Natl. Acad. Sci. USA, 1985, 82(16), 5255-5259.)| false 10.1073/pnas.82.16.5255
Schulze-Gahmen U. Wilson I.A. Monoclonal antibodies against an identical short peptide sequence shared by two unrelated proteins Pept. Res. 1989 2(5) 322-331.
Paul W.E. Fundamental Immunology Wolters Kluwer Health/Lippincott Williams & Wilkins Philadelphia 2013.
Mittelman A. Tiwari R. Lucchese G. Willers J. Dummer R. Kanduc D. Identification of monoclonal anti-HMW-MAA antibody linear peptide epitope by proteomic database mining J. Invest. Dermatol. 2004 123(4) 670-675.
Linke W.A. Hamdani N. Gigantic business: titin properties and function through thick and thin Circ. Res 2014 114(6) 1052-1068.
Kanduc D. Potential cross-reactivity between HPV16 L1 protein and sudden death-associated antigens J. Exp. Ther. Oncol. 2011 9(2) 159-165.
Capone G. Kanduc D. Peptide sharing between Bordetella pertussis proteome and human sudden death proteins: a hypothesis for a causal link Future Microbiol. 2013 8(8) 1039-1048.
Pavia A.T. Influenza vaccine effectiveness: mysteries enigmas and a few clues J. Infect. Dis. 2016 213(10) 1521-1522.
Kanduc D. Shoenfeld Y. Inter-pathogen peptide sharing and the original antigenic sin: solving a paradox Open Immunol. J. 2018 8 16-27.
Bell P.J. Viral eukaryogenesis: was the ancestor of the nucleus a complex DNA virus? J. Mol. Evol. 2001 53 251-256.
Forterre P. The origin of viruses and their possible roles in major evolutionary transitions Virus Res. 2006 117 5-16.
Kanduc D. The comparative biochemistry of viruses and humans: an evolutionary path towards autoimmunity Biol. Chem. 2018 doi: 10.1515/hsz-2018-0271.