Molecular similarities between the genes for Trypanosoma cruzi microtubule associated proteins, mammalian interferons, and TRIMs

doi:10.21203/rs.3.rs-4267184/v1

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Molecular similarities between the genes for Trypanosoma cruzi microtubule associated proteins, mammalian interferons, and TRIMs

https://doi.org/10.21203/rs.3.rs-4267184/v1

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Initial studies using bioinformatics analysis revealed DNA sequence similarities between Trypanosoma cruzi GenBank M21331, coding for Antigen 36 (Ag 36), and Tripartite Motif (TRIM) genes. TRIM40 showed 9.7% identity to GenBank^® M21331 and four additional TRIM genes had identities greater than 5.0%. TRIM37 showed a continuous stretch of identity of 12 nucleotides, that is at least 25% longer than any of the other TRIMs. When we extended our analysis on the relationships of GenBank M21331 to further innate immune genes, using the Needleman-Wunsch (NW) algorithm for alignment, identities to human IFN-α, IFN-β, and IFN-γ genes of 13.6%, 12.6%, and 17.9%, respectively, were found. To determine the minimum number of genes coding for proteins closely related to Ag 36, a BLAST-p search was conducted with it versus the T. cruzi genome. The BLAST-p search revealed that T. cruzi GenBank M21331 had 14 genes sequences homologous to Microtubule Associated Protein (MAP) genes with 100% amino acid sequence identity. To verify the similarities in non-human genes, a study comparing TRIM21 region sequences among mammalian species to the comparable human TRIM21 region showed that related sequences were also present in 11 mammalian species. The MAP genes homologous to Ag 36 form a family of at least 14 genes which mimic human immune genes in the IFN and TRIM families. This mimicry is of gene sequences, and not their protein products or epitopes. These results appear to be the first description of molecular mimicry of immune genes in humans by a protozoan parasite.

Trypanosoma cruzi

Antigen 36

Interferons

TRIM genes

Molecular mimicry

Chagas' disease (also called American trypanosomiasis) causes a spectrum of disease in humans from infection with the parasite Trypanosoma cruzi. Today, an estimated 10 to 20 million human individuals and countless susceptible mammalian species are infected with this parasite. It has been estimated that an additional 100 million people may be at risk of infection (Pan and Winkler 1995). Unfortunately, these numbers have not decreased over several decades. As a primary neglected tropical disease and a parasitic infection with the highest impact of morbidity in the Americas, several methods of intervention must be evaluated and used to be able to prevent further spread of the disease. These include: (a) the use of therapeutics, (benznidazole and nifurtimox) which have only recently (2017 and 2020, respectively) been FDA approved for use in children ages 2 to 12 years old (benznidazole) and <18 years weighing ≥5.5 lbs (≥2.5 kg) (nifurtimox) with Chagas’ disease. However, side effects are common, frequent, and severe, with increasing age. In addition, some indication exists that these drugs only affect parasites in the early phases and not in the chronic stages of infection. (b) Methods such as insect vector control through the use of bed nets, insecticides, and improved housing conditions. (c) Serological diagnostic tests to identify infected patients or donated blood products that may be used in transfusions and organ transplants (Gudino and Linares 1990). It is of note that the recognition of this parasite as a potential threat to the US blood supply occurred in 1992 when several biopharmaceutical companies developed diagnostic tests to identify this disease (Pan et al. 1992; Pan and Winkler 1995). In 1995 the FDA accepted a 510(k) diagnostic test (Enzyme Immunoassay) for Chagas’ disease (Pan et al. 1992; Pan and Winkler 1995; Brashear et al. 1995; Winkler et al. 1995). Progressive improvements to identify several highly antigenic T. cruzi molecules reactive with human chagasic antiserum were made in subsequent years (2006-2011); the Association for the Advancement of Blood and Biotherapies (AABB), the FDA, CDC, and WHO have now recognized this disease as one of the 13 donor screening assays for Infectious Agents; and (d) Immunological and molecular biological approaches to study, characterize, and recognize antigenic molecules which are involved in mounting a protective immune response or to arrest further progression of debilitating illness, and to understand the immunological mechanisms of how the parasite may evade the immune response at the gene level. Further knowledge with the use of these disciplines may lead to the development of preventative or treatment measures such as vaccines and therapeutics. Therefore, our focus has been to search, identify, and study highly antigenic T. cruzi molecules reactive with human chagasic antiserum (Pan and McMahon-Pratt 1989; Pan et al. 1992; Pan and Winkler 1995; Brashear et al. 1995; Winkler et al. 1995; Winkler and Pan 2010).

In earlier investigations, we identified one cloned gene from T. cruzi (Brazil strain) amastigotes from axenic culture (Pan 1978), (sequenced by the Sanger method) (Sanger et al. 1977), which was found to be identical to the repetitive antigen Clone 36, "Antigen 36" (Ibanez, et al. 1988), and also the subsequently described JL9 Antigen (Levin et al. 1990); (Winkler et al. 1998; Winkler and Pan 2010). An initial search of the cloned T. cruzi amastigote gene sequence in the Wisconsin Package (Womble 2000), with our DNA sequence disclosed similarity to human Ro52 with the translated sequence in the second reading frame of Ag 36. Direct comparison of the Ag 36 DNA sequence with Ro52 DNA sequence revealed a 70% identity in one sequence of 44 nucleotides between the Ag 36 DNA sequence and TRIM21, the gene for human Ro52 (Winkler et al. 1998). Once the function of TRIM21 was identified, we proposed that there may be a link between it and the gene for Ag 36 identified in Chronic Chagas Cardiomyopathy (CCC) (Winkler and Pan 2010). Ro52 is expressed in the immune system as a predominantly cytoplasmic protein that can be upregulated and translocated to the nucleus in a pro-inflammatory environment.

In this study, we further query TRIM genes, in addition to innate mammalian immune genes, for any such extended sequence similarities using established bioinformatic tools (Needleman and Wunsch 1970; Whelan et al. 2013). TRIM genes are a large family of mammalian and vertebrate genes, which share homologous domains (Ozato et al. 2008; Sjöstrand et al. 2020). Many of these genes code for E3 Ubiquitin ligases, and many of them function in regulating innate immunity and immunity to viruses and cancer (Meroni and Diez-Roux 2005; Nisole et al. 2005; Noguchi et al. 2011). For example, TRIM21 is an E3 Ubiquitin ligase that modifies transcription factors for IFN-α and IFN-β and other cytokines, thereby dampening (or stimulating) IFN gene transcription (Kong et al. 2007; Higgs et al. 2008). Knock out of TRIM21 in mice strains showed that they were susceptible to tissue inflammation and systemic autoimmunity after injury induced by skin tagging (Espinosa et al. 2009). We proposed that the partial gene homology between TRIM21 and Ag 36 may cause down-regulation of Ro52, leading to the autoimmunity of CCC (Hidron et al. 2010; Winkler and Pan 2010). We also proposed that for the parasite that downregulation may be beneficial during its invasion of macrophages by blocking TRIM21 stimulation of innate immunity. It would be useful to explore any similarities between Ag 36 and the genes of other mammalian TRIM21 genes to validate the sequence similarity observed between human TRIM21 and the T. cruzi Ag 36 gene.

The complete sequence of the nuclear genome of T. cruzi (CL-Brener) was published by El-Sayad et al. 2005, and subsequently DeCuir and his team (2021) verified the sequence with T. cruzi (strain SC43). This sequence by these scientists and others enabled (a) our description of T. cruzi genes homologous to Ag 36 by a BLAST-p search of its amino acid sequence versus the T. cruzi genome; (b) our finding that there are human TRIM family genes similar to them; and (c) our additional discovery here that T. cruzi Ag 36 gene sequence is similar to human IFN- α, β, and γ genes. The T. cruzi MAP gene similarities we describe here are a new category of molecular mimicry where protozoan genes mimic human immune cell genes.

In this work, we verify the findings in human genes as we extend the comparison of DNA sequences of Ag 36 to eighteen additional mammalian TRIM21 sequences, using the Needleman-Wunsch (NW) algorithm to determine partial sequence similarities, and to determine if the similarities observed were a unique phenomenon in primates, or whether they extend to other mammals.

Cloning of amastigote genes

We identified one cloned gene from T. cruzi (Brazil strain) amastigotes grown in axenic culture (Pan 1978), which was sequenced by the Sanger method (Sanger et al. 1977), and found to be identical to the repetitive antigen Clone 36, "Antigen 36" (Winkler et al. 1998).

Blast search to determine number of Ag 36 homologues

The GenBank M21331 gene was translated into its amino acid sequence using the translation tool at https://usegalaxy.org (Blankenberg et al. 2007; Afgan et al. 2016) and the sequence entered in the BLAST-p search box, to determine homologous genes in the T. cruzi genome. The BLAST-p algorithm was selected at https://ncbi.nlm.nih.gov/Blast.cgi. The searched database entered was Trypanosoma cruzi taxid 5393; and the first 100 most homologous genes (in order of their homology to GenBank M21331) and their amino acid sequences were downloaded and saved as a text file. The “e value” noted in Table 1 is the probability that this result happened by random chance.

Needleman-Wunsch (NW) alignments

To align and compare human or mammalian genes with the GenBank M21331 gene sequence, the Needleman-Wunsch (NW) algorithm (Needleman and Wunsch 1970) was selected at https://usegalaxy.org or https://usegalaxy.eu (Blankenberg et al. 2007; Afgan et al. 2016). The NW Algorithm is the standard method of aligning and comparing two amino acid or two gene sequences with the fewest gaps, with a significance score assigned to each alignment. The NW significance score is a measure of the extent to which gaps were needed to achieve the alignment when considering their entire length. A higher score indicates that fewer gaps were inserted. The genes were downloaded from GenBank at https://www.ncbi.nlm.nih.gov/nucleotide/. The saved sequences were sequentially entered into the workflow at https://usegalaxy.eu. The results of the NW alignments are stored in workflows by date at https://usegalaxy.eu (the human genes) or at https://usegalaxy.org (Blankenberg et al. 2007; Afgan et al. 2016) (mammalian genes), (available free to view). The dataset and workflows are stored at the two persistent and web links (Data Availability Statement below).

Mammalian TRIM sequences, human IFN, and (Interleukin) IL-1 α and IL-2 sequences were retrieved from https://ncbi.nlm.nih.gov/gene and the sequences compared to the Ag 36 gene (GenBank M21331) with tools at https://usegalaxy.org (Blankenberg et al. 2007; Afgan et al. 2016). To determine gene sequence similarity, gene sequences were also aligned by the NW algorithm(Needleman and Wunsch 1970). The dataset and workflows are stored at https://usegalaxy.org (Blankenberg et al. 2007; Afgan et al. 2016) (Data Availability Statement below).

Phylogenetic comparison of TRIM21 mammalian sequences

Sequences of TRIM21 genes from 19 mammalian species, other than human, were also retrieved from GenBank and sequences compared to the Ag 36 gene (GenBank M21331) with tools at https://usegalaxy.org (Blankenberg et al. 2007; Afgan et al. 2016), and viewable under the username martinawinklerphd (Data Availability Statement below). The mammalian TRIM21 genes analyzed represented the following: primates (human, chimpanzee), in addition to mouse, rat, gerbil, dog, cat, nine-banded armadillo, shrew, lynx, ferret, marmoset, bat, sheep, cow, deer, horse, aardvark, rabbit, and goat. Nucleotides 856 to 916 of the above mammalian non-human TRIM21 genes were aligned with GenBank M21331 by the NW algorithm (Needleman and Wunsch 1970). This nucleotide stretch of TRIM21 was the most similar section found to GenBank M21331 by the NW algorithm. This complete set of mammalian gene sequences was not available for the other TRIMs.

BLAST-p search of GenBank with Ag 36 protein sequence

To determine the number of homologues of Ag 36 in the T. cruzi genome, a BLAST-p search of the https://ncbi.nlm.nih.gov/Blast.cgi database with the Ag 36 protein sequence was conducted, which revealed 14 T. cruzi GenBank entries that have a “100% positive” match (Table 1).

Table 1 Results of the BLAST-p of Ag 36 amino acid sequence versus the T. cruzi genome performed at and retrieved from http://ncbi.nlm.nih.gov

GenBank Accession Number	% Identity	Length (nucleotides)	Mismatches (nucleotides)	Nucleotide Start	Nucleotide End	e value*	% Positives
RNC30406.1	97.368	38	1	111	148	4.14E-17	100
PWU97874.1	97.368	38	1	107	144	8.82E-17	100
AF8288323.1	97.222	36	3	33	68	2.35E-15	100
AF8288347.1	97.368	38	1	145	182	1.89E-16	100
AF8288347.1	96.667	30	9	1	30	4.22E-11	100
PWU84425.1	97.368	38	1	328	365	1.94E-16	100
PWV17283.1	97.368	38	1	182	219	3.99E-16	100
PWU83738.1	97.368	38	1	107	144	5.01E-16	100
PWU83738.1	97.368	38	1	335	372	5.01E-16	100
PWU83738.1	97.368	38	1	373	410	5.01E-16	100
PWU83738.1	97.368	38	1	411	448	5.01E-16	100
PWU83738.1	97.368	38	1	449	486	5.01E-16	100
PWU83738.1	97.368	38	1	487	524	5.01E-16	100
XP_809567.1	97.297	37	1	41	77	8.11E-15	100

* The “e value” is the probability that this result happened by random chance

The e values in Table 1 indicate that these results all have probabilities less than 10^-15 of occurring by chance. Since these genes code for proteins referred to in GenBank listings as “Microtubule Associated Protein” (MAP), or “Putative Microtubule Associated Protein,” or “Hypothetical Microtubule Protein,” we will refer to these as MAP genes. Thirty-seven of the BLAST-p results have sequences greater than 94% identical to Ag 36. These were within the proteins found in four entries, GenBank Accession numbers KAF8288323.1; PWU83737.1; PWU83737.1; and RNC30406.1, implying that the sequences are repeated within each gene entry.

Ag 36 gene comparison to TRIM genes

Since TRIM genes share DNA sequence identities between their conserved domains(Ibañez et al. 1988), and TRIM21 had shown sequence similarity to Ag 36 in previous studies (Winkler et al. 1998), we chose to test the sequences of 43 human TRIM genes for similarity to the GenBank M21331. Table 2 demonstrates that human TRIM40 had a 9.7% identity.

Table 2 Results, as percentages of identity found of the Needleman-Wunsch (NW) alignments for each of the listed human TRIM genes compared to GenBank M21331

TRIM Gene	% Identity	NW Score*	TRIM Gene	% Identity	NW Score*
40	9.7	130.0	27	2.7	140.0
73	6.4	140.0	65	2.5	150.5
58	5.4	142.0	37	2.4	132.5
10	5.3	131.5	26	2.3	145.5
43	5.0	148.0	39	2.2	147.5
64	4.9	146.0	62	2.2	156.5
61	4.8	118.5	35	1.8	154.0
6	4.5	121.0	23	1.7	105.0
7	4.5	121.0	25	1.4	142.0
31	4.2	145.5	38	0.9	133.5
60	4.2	119.5	56	0.8	167.5
15	4.0	144.0	68	0.8	152.0
17	4.0	154.0	28	0.6	144.0
48	4.0	124.5	8	0.4	160.0
21	3.9	139.0	41	0.4	162.5
47	3.6	141.5	63	0.4	154.0
50	3.6	166.5	5	0.3	142.5
75	3.6	148.0	69	0.2	144.5
49	3.4	125.0	24	0.1	158.5
11	2.8	146.5	33	0.1	150.0
34	2.8	115.0	44	0.1	163.5
52	2.8	145.0

* The NW alignment score is a measure of the extent to which gaps were needed to achieve the alignment; a higher score indicates that fewer gaps were inserted

The NW alignment of GenBank M21331 with the gene for human TRIM40, GenBank NG_033972.1_cds_NP_001273562.1_1, is shown in Figure 1.

The length of continuous match is as important as the overall percent identity in evaluation of matches. Whereas TRIM37 had only 2.4% overall identity (Table 2), inspection of the alignment of its gene, GenBank NM_015294.6_cds_NP_056109.1_1, with GenBank M21331, is shown in Figure 2, where a continuous stretch of 12 nucleotides are identical between its gene and Ag 36.

The next longest continuous matches observed of all the TRIM matches were in TRIM17 and TRIM52 with continuous stretches of nine nucleotides each, only 75% that observed with TRIM37. All these identities have NW significance scores well over 10, which indicate from the algorithm that they cannot be due to random occurrence. Thirteen of the human TRIM genes showed 4.0 to 6.4% sequence identity. Twenty-eight TRIM genes had less than 4.0% identity (Table 2).

Ag 36 gene comparison to IFN and IL genes

Since TRIM proteins are intrinsic to innate immunity, we examined GenBank M21331 for similarity to several key cytokines involved in innate immunity, for example, IFNs and ILs. Table 3 displays the results for human IFN-α, IFN-β, and IFN-γ, as well as human IL-1 α and human IL-2.

Table 3 Results of the Needleman-Wunsch (NW) alignments of IFNs, IL-1 α or IL-2 with GenBank M21331, showing percentages of identity found for each alignment

Human Gene	% Identity	NW Score*
INF-α	13.6	134.0
INF-β	12.6	102.0
INF-γ	17.9	82.5
IL-1 α	9.8	127.5
IL-2	12.5	85.5

*The NW alignment score is a measure of the extent to which gaps were needed to achieve the alignment; a higher score indicates that fewer gaps were inserted.

Human IFN-γ showed 17.9% identity; though its NW significance score of 82.5 was less than the other IFNs examined. Human IFN-α showed 13.6% identity with a higher NW score (134.0). Note that there is a stretch of similarity (23/34) in nucleotides 361-395 of human IFN-α, GenBank J00210.1_cds_AAB59403.1_1 which demonstrates the significance of this comparison with GenBank M21331 (Figure 3). Human IL-2 showed a 12.5% identity and human IL-1 α showed a 9.8% identity.

Comparison of TRIM21 (nucleotides 856-916) to Ag 36 in mammals

To further verify the similarities found between human immune genes and T. cruzi MAP genes, we compared GenBank M21331 with 19 other mammalian TRIM21 genes. Therefore, an assessment to associate these mammalian TRIM21 genes to the T. cruzi Ag 36 DNA sequence was accomplished using the NW algorithm in the https://usegalaxy.org (Blankenberg et al. 2007; Afgan et al. 2016) bioinformatics tool base. The nucleotide stretch (856-916) of TRIM21 was the most similar section found with GenBank M21331 by the NW algorithm. This nucleotide stretch of TRIM21 resulted in the greatest percentage of homology with human (68%), followed by chimpanzee (60%), dog (57%), and shrew (50%) (Table 4).

Table 4 The mammalian TRIM21 genes listed were compared to GenBank M21331 by the Needleman-Wunsch (NW) Alignment at https://usegalaxy.org, and the nucleotides that were identical in the TRIM21 nucleotide range of 856 to 916 were counted (column 3) and divided by 60, the total nucleotides in that range, to provide the percent identity to TRIM21

Mammal (Common Name)	Genus species	Number of Nucleotides Identical to TRIM21	% Identity to TRIM21*
Human	Homo sapiens	41/60	68
Chimpanzee	Pan troglodytes	36/60	60
Dog	Canis familiaris	34/60	57
Shrew	Sorex araneus	30/60	50
Ferret	Mustela putorius furo	27/60	45
Bat, common Vampire	Desmodus rotundus	26/60	43
Cat, domestic	Felis catus	24/60	40
Armadillo (9 band)	Dasypus novemcinctus	23/60	38
Aardvark	Orycteropus aferaardvark	20/60	33
Deer, White tailed	Odocoileus virginianus	19/60	32
Rabbit	Oryctolagus cuniculus	19/60	32
Rat, Brown	Rattus norvegicus	0/60	0
Mouse	Mus musculus	0/60	0
Gerbil	Meriones unguiculatus	0/60	0
Sheep	Ovis aries	0/60	0
Cow	Bos taurus	0/60	0
Horse	Equus ferus caballus	0/60	0
Goat, domestic	Capra hircus	0/60	0
Marmoset	Callithrix jacchus	0/60	0
Lynx	Lynx canadensis	0/60	0

* The complete set of mammalian gene sequences was not available for the other TRIMs.

Seven other species showed partial homologies in the compared region of 32% to 45%. The nine other mammalian TRIM21 genes shown in Table 4 had no significant similarity (<2%) in this region. Of those mammalian TRIM21 genes showing similarity, the percentage of identity correlate substantially with the phylogeny of these mammals. The greater the distance in phylogeny, the fewer percent matches in the relevant TRIM21 regions. It would be of interest to compare the similarity of additional TRIMs however, the complete set of mammalian gene sequences was unfortunately not available.

The purpose of this study was to compare DNA sequences between T. cruzi GenBank M21331, which codes for Ag 36, and human immune genes using bioinformatics analysis. The NW Algorithm was used to compare the GenBank M21331 gene sequence to TRIM genes, and human IFN and IL genes. This algorithm produced a Significance score for each comparison. The score is a probability function that quantitates the possibility that the result could occur from random associations and penalizes gaps that are inserted to make the matches. Generally, a score over 10 indicates non-randomness. All the significant identity results had NW Significance scores over 82 for IFNs (Figure 1), and over 100 for the TRIM comparisons (Table 2), indicating that the identities are not random or by chance. In addition, we find stretches, for example of 68% similarity with human IFN gene compared with GenBank M21331. It is of note that human INF- α had a 13.6% identity (134.0 score); INF-β had a 12.6% identity (102.0 score); and INF-γ had a 17.9% identity (82.5 score). In addition, human IL-1 α had a 9.8% identity with a 127.5 score and IL 2 had a 12.5% identity with a 85.5 score to GenBank M21331 (Table 3). Therefore, the results indicated similarity of GenBank M21331 with TRIM genes, IFN, IL-1 α, genes that code for innate immunity, and IL-2 for adaptive immunity. In addition, a BLAST-p from https://blast.ncbi.nlm.nih.gov/Blast.cgi was used to determine the number and identity of genes in the T. cruzi genome that can produce the Ag 36 amino acid sequence. That BLAST-p revealed that the Ag 36 gene of T. cruzi had 14 homologous genes sequences (MAP genes with 100% amino acid sequence identity to GenBank M21331).

The IFN gene identities are compelling since IFN-γ stimulates T-cells that recognize T. cruzi, and IFN-α and IFN-β stimulates innate immune cells during T. cruzi intracellular infection (Hidron et al. 2010; Winkler and Pan 2010). We propose at the T. cruzi mRNAs for the 51 MAP-like proteins (14 homologues plus 37 with 94% identity), may affect expression of IFN-α or IFN-γ, for example, if the parasite mRNAs found their way into the host cell. As evidence that RNAs can find its way into host cytoplasm, Bayer-Santos et al. (2013) report that extracellular vesicles secreted from metacyclic T. cruzi trypomastigotes contain parasite mRNAs, in addition to other varieties of small and larger RNAs. Similarly, the transfer to host of parasite mRNA may also affect (by an unknown mechanism) translation or regulation of RNAs so that the levels of TRIM proteins such as human TRIM37, TRIM40, or TRIM21 (Bayer-Santos et al. 2013) are affected.

The human TRIM37 genes notably showed regions of high sequence identity to MAP genes, with 12 consecutive nucleotide matches to GenBank M21331. Two possibilities that are known for down-regulation of TRIM37 by hybridization of a complementary RNA are RNA silencing, and RNA Interference. RNA silencing requires at least 17 to 19 complementary nucleotides (Ge et al. 2010) whereas RNA Interference requires at least 19 complementary nucleotides (Lv et al. 2019). Therefore, 12 or fewer nucleotides will not suppress TRIM37 by these means. However, it is possible that there is an unknown mechanism for them to recognize and inhibit TRIM37 through host RNA, soluble interfering RNA (siRNA), or micro-RNA. In this regard, it is intriguing that in Mulibrey nanism syndrome (a rare autosomal recessive congenital disorder) that mutated TRIM37 gene causes severe cardiomyopathy and growth failure of the muscles, liver, brain and eye among other birth defects when mutated in humans (Avela et al. 2000; Eerola et al. 2007; Brigant et al. 2019), which is similar to the cardiac pathogenesis that occurs in Chagas’ disease.

TRIM40 showed the highest identity of any TRIMs to Ag 36 gene. Similar to TRIM37 and TRIM21, TRIM40 is also an E3 ubiquitin ligase that plays a vital role in mammalian immune signaling pathways and may also target proteins for destruction (Jia et al. 2021). This TRIM multigene family has a key regulatory role during the immune response against pathogens. When pathogens are recognized by the immune system through the pattern-recognition receptors, several immune responses are initiated, such as the production of interferons (IFNs), leading to the expression of TRIM proteins. The upregulation of TRIM genes in response to IFN-γ has been reported in human monocytes and macrophages. Cell invasion into these types of immune cells by T. cruzi and a type I IFN response has been reported (Costales 2017). Over-expression and upregulation of TRIM40 may be linked to the control of both IFNs and the stability of the cytoskeleton network and its function(s). A three-dimensional cytoskeletal network is formed which consists of actin, microtubules, and intermediate filaments which are interlinked by protein interactions. Microtubule-associated proteins (MAPs) belonging to the MAP1, 2, 4 family, Tau proteins, and actin are involved in crosslinking or bridging these cytoskeletons (Patel et al. 2009; Mohan and John 2015). TRIM40 may also modify transcription factors for IFN and other cytokines similar to TRIM21 in T. cruzi, and is intriguing since there is a 9.7% identity to GenBank M21331. TRIM40 directly targets Rho-associated coiled-coil-containing protein kinase 1 (ROCK1), which is involved in supporting cell-cell junctions, decreasing the phosphorylation of signaling factors in stabilization and the development of actin. This causes an inflammatory response from failure of the function of the epithelial barrier. The association of actin filaments with microtubules is crucial for cell division, migration, vesicle and organelle transport, and axonal growth (Patel et al. 2009; Mohan and John 2015). TRIM40 has also been shown to be pathogenic driver of inflammatory bowel disease (IBD) (Kang et al. 2023) and this association may perhaps have an effect on Chagas’ disease megacolon often seen in patients with Chronic Chagas’ disease. The Ag 36 gene of T. cruzi, GenBank M21331, was found to have 14 homologous and 37 highly similar genes in the T. cruzi genome. Its prevalence in the genome is reflected in its use in next-generation tests for antibodies to Chagas’ disease, where one of its peptides, p12 (a MAP - TcCLB.511633.79) (Ibañez et al. 1988), showed 76% sensitivity in 61 samples of infected sera (Mucci et al. 2017). It is therefore conserved in a majority of strains of T. cruzi and can perhaps be used universally where Chagas’ disease testing is necessary (Negrette et al. 2008; Majeau et al. 2024).

When human IFN genes were compared with Ag 36 (GenBank M21331), IFN-α was 13.6% identical, IFN-β was 12.6% identical, and IFN-γ was 17.9% identical. Studies by Cunha-Neto et al. 2005 and Marin-Neto et al. 2007 suggest that IFN-γ signaling in the myocardium is associated with human CCC as well as with membrane cofactor protein-1, which is increased with the expression of atrial natriuretic factors. These both are markers of cardiomyocyte hypertrophy and heart failure in neonatal murine cardiomyocytes. These findings suggest that IFN- γ mediated chronic myocardial inflammation could contribute to the pathogenesis of CCC. In addition, the cytokine profile associated with Chagas myocarditis is shifted toward Th1 cytokines, with elevated IFN- γ levels, and decreased IL-10 levels which may theoretically prolong an ongoing inflammatory process (Gomes et al. 2003; Marin-Neto et al. 2007; Hidron et al. 2010). Recent studies of a useful mouse model of CCC revealed the additional roles of fibrosis and residual parasites and the associated signaling pathways in CCC (Hoffman et al. 2019, 2021).

As an additional study, the significance of gene similarity of Ag 36 to human TRIM21 was verified by comparing the T. cruzi Ag 36 gene sequence with various mammalian TRIM21 gene sequences (TRIM21 being the most sequenced of the mammalian TRIM genes). These results correlated with the mammalian phylogeny. Primate TRIM21 was most similar to Ag 36, followed by dog, shrew, ferret, bat and cat. More distant mammals to humans, such as sheep, rats, and mice, were not similar. Of these species, humans and dogs have been shown to have CCC after T. cruzi infection (Jansen et al. 2017).

The 14 MAP genes homologous to Ag 36 form a family of genes which mimic human immune genes in the IFN and TRIM families. This mimicry is mimicry of gene sequences and not of their protein products or epitopes that might be associated with autoimmunity. Molecular mimicry associated with T. cruzi has been hypothesized to be associated with autoimmunity, due to mimicry of surface antigens and epitopes, resulting in symptomology of CCC (Cunha-Neto et al. 2006). The underlying mechanisms are due to activation of T- and B-cells by the parasite (Eisen and Kahn 1991; Gironès et al. 2005) with increased local expression of the cytokines IFN-γ, TNF-α, IL-6, and IL-4, as well as HLA class I/class II molecules and adhesion molecules (Iwai et al. 2005).

In Plasmodium (malaria) infections, where RIFIN proteins mimic the human Major Histocompatibility Complex (MHC), to block human killer cells from recognizing malaria infected red blood cells (Harrison et al. 2020). RIFINs are a second gene family (rif), which is associated with variant proteins (var) at subtelomeric sites in the malaria genome, that encodes clonally variant proteins (RIFINs) that are expressed on the surface of red cells infected with P. falciparum. An especially vivid example of parasite molecular mimicry in T. cruzi was found by Van Voorhis et al. (1991), who describe a 12-amino acid peptide sequence that mimics an antigenic epitope in human nerve tissue. In their study, humans with T. cruzi infection were liable to nerve destruction exhibiting megacolon and megaesophagus conditions, and their sera contained antibodies to the 12 amino acid peptide sequence and the nerve antigen sequence. This molecular mimicry by T. cruzi of a human nerve protein is analogous to our results, which is mimicry of human immune genes by T. cruzi genes. Although molecular mimicry has been reported between host and pathogen in other parasites (Abu-Shakra et al. 1999), it appears that ours is the first report and investigation of mimicry of human immune genes by a protozoan parasite.

Another related phenomenon occurs in Trypanosoma brucei spp. (African Trypanosomes), which uses antigenic variation to evade the immune response (Cross et al. 2014). This mechanism consists of a successive expression of a single or a multiple number of antigenic surface variants taking place within the mammalian host. Once the host immune response controls the foremost variant the parasite switches to a new variant, thus again evading the immune response and the cycle continues. This one factor at a time (OFAT) method is henceforth an effective strategy when the parasite is continuously exposed to antibody-mediated immune modulated mechanisms. This is an example of a sophisticated genetic program by a Trypanosome to overcome the host immune response. Although in the order Kinetoplastida, T. cruzi, unlike T. brucei, takes a dissimilar approach to antigenic variation by producing multiple, very large families of repetitive genes which may encode surface and secreted proteins. These are expressed concurrently instead of serially. It is hypothesized that this method may assist the amastigote form of T. cruzi to survive and propagate in susceptible hosts and evading recognition by T-cells. Additionally, investigations into the biological mechanisms of T. cruzi are perplexing due to the multifaceted nature and unique characteristics of its genes. Over 50% of the T. cruzi genome is composed of repetitive sequences, simple tandem repeats (El-Sayed et al. 2005; De Pablos and Osuna 2012); and numerous families of surface proteins (e.g. mucins and mucin-associated surface proteins (Di Noia et al. 1995; Herreros-Cabello et al. 2020); and trans-sialidases (Pan and McMahon-Pratt 1989; Low and Tarleton 1997; Herreros-Cabello et al. 2020).

Trypanosoma cruzi largely avoids the adaptive immune system during its intracellular residence but is still faced with attack from the host cell innate immune system. The T. cruzi MAP genes partial identities to those human immune genes, which are conserved over the hundreds of millions of years separating Protozoa and Humans, may be relevant to the parasite’s resistance to the mammalian innate immune system during infection. Experiments to test this hypothesis would measure levels of the host IFN-α, IFN-β, and IFN-γ and TRIM37, TRIM40 and TRIM21 proteins during infection compared with non-infected cells. In the case of TRIM21, quantitation of the proteins in infected or non-non-infected cells could be accomplished by commercial immunoassay. Measurement could also be accomplished by selected ion protein mass spectrometry to quantitate those proteins. Lower quantities per cell of these proteins compared with non-infected controls may provide evidence that these gene similarities affect the expression of these immune system proteins.

Acknowledgements

The authors would like to thank Abbott Laboratories and our colleagues where the foundational investigations were performed. The Galaxy server that was used for some calculations is in part funded by Collaborative Research Centre 992 Medical Epigenetics (DFG grant SFB 992/1 2012) and German Federal Ministry of Education and Research (BMBF grants 031 A538A/A538C RBC, 031L0101B/031L0101C de.NBI-epi, 031L0106 de.STAIR (de.NBI)).

Author contributions

All authors contributed equally to this work in the study, research, conception and design. In addition, both authors contributed correspondingly to material preparation, data collection, interpretation and analysis. Both authors wrote, read and approved the final manuscript. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Definitions

Antigen 36 (Ag 36) – (clone A2; clone 36; Tc36; JL9) – The tandemly repeated T. cruzi antigen originally reported by Ibanez and colleagues (1988) which is highly reactive with Chagasic sera.

GenBank M21331 - GenBank^® is a database that contains publicly available nucleotide sequences for genus/species organisms. The library is obtained through submissions from laboratories and batch submissions from large-scale sequencing projects. T. cruzi GenBank M21331 encodes for Antigen 36 (Ag 36).

MAP (Microtubule Associated Proteins) – Microtubule associated proteins regulate assembly and stability of microtubules. Microtubules constitute a major part of the cytoskeleton and are important in cytoskeletal rearrangements during neuronal growth, axon guidance, and synapse formation. Ag 36 gene of T. cruzi has 14 homologous genes sequences (MAP genes with 100% amino acid sequence identity) to GenBank M21331.

Ro52 – Ro52 is the protein product of TRIM21.

TRIM (Tripartite Motif) - TRIM proteins are a family of ubiquitin E3 ligases which share a characteristic N-terminal tripartite motif consisting of a highly conserved order of three domains: the interesting new gene (RING) domain, one or two B-box domains and a coiled coil region.

Data availability

The datasets generated during and/or analyzed during the current study are available in the online Galaxy repositories:

https://usegalaxy.eu/u/martinawinklerphd/h/copy-of-copy-of-mammalian-trim-genes-compared-with-antigen-36 and

https://usegalaxy.org/u/martinawinklerphd/h/ag36-and-mammalian-trim21-homologies

These bioinformatics workflows are available to all, but registration (which is free) is required to view the results.

Web references

Genes from http://www.ncbi.nlm.nih.gov/gene

Species’ GenBank accession numbers at http://www.ncbi.nlm.nih.gov

Nucleotide sequence database from https://www.ncbi.nlm.nih.gov/nucleotide/

BLAST-p utlilty at https://blast.ncbi.nlm.nih.gov/Blast.cgi

NW algorithm alignment and comparison tool at https://usegalaxy.org or https://usegalaxy.eu

Homo sapiens TRIM21

IFN-α GenBank J00210.1_cds_AAB59403.1_1

TRIM37 GenBank NM_015294.6_cds_NP_056109.1_1

TRIM40, GenBank NG_033972.1_cds_NP_001273562.1_1

Trypanosoma cruzi Clone 36 Antigen GenBank M21331

Statements and Declarations

Ethics approval Not applicable.

Financial interest The authors have no relevant financial or non-financial interests to disclose.

Consent to participate Not applicable.

Consent for publication Not applicable.

Competing interests Not applicable.

Open Access

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Molecular similarities between the genes for Trypanosoma cruzi microtubule associated proteins, mammalian interferons, and TRIMs

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